Updated on 2023/01/16

写真a

 
TOMIDA Shuta
 
Organization
Okayama University Hospital Associate Professor
Position
Associate Professor
External link

Degree

  • 博士(工学) ( 名古屋大学 )

Research Interests

  • Bioinformatics

  • マイクロアレイ

  • 肺癌

  • 腫瘍マーカー

  • バイオマーカー

  • Analysis of skin microbiome

  • Comparative genome analysis

  • マイクロRNA

  • 予後予測

  • 浸潤・転移

  • 発現プロファイリング

  • Analysis of gene expression profile

  • Analysis of clinical sequencing

  • 感受性予測

  • パスウェイ解析

  • 再発予測

Research Areas

  • Others / Others  / Laboratory medicine

  • Life Science / Cardiovascular surgery

  • Informatics / Life, health and medical informatics

  • Life Science / Respiratory medicine

  • Life Science / Respiratory surgery

  • Life Science / Dermatology

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Research History

  • Okayama University   ゲノム医療総合推進センター   Associate Professor

    2019

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  • Okayama University   医歯薬学総合研究科

    2015 - 2019

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  • Kinki University   Faculty of Medicine   Lecturer

    2013 - 2015

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  • University of California Los Angeles

    2009 - 2013

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  • Nagoya University   大学院・医学系研究科   Assistant Professor

    2006 - 2008

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  • Aichi Cancer Center Research Institute

    2003 - 2005

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Professional Memberships

Committee Memberships

  • 日本癌学会   評議員  

    2018   

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    Committee type:Academic society

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Papers

  • Persistent alteration of the skin microbiome in patients with skin rash after receiving EGFR inhibitor treatment. Reviewed International journal

    Atsuko Ashida, Shuta Tomida, Tokuro Iwabuchi, Yuki Sato, Yukiko Kiniwa, Ryuhei Okuyama

    Experimental dermatology   2022.12

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)  

    The pathological mechanism responsible for EGFR inhibitor (EGFRI)-induced skin rash remains unclear. Recent studies reveal associations between skin dysbiosis and skin inflammatory diseases. This study aimed to examine whether skin dysbiosis is associated with EGFRI-induced skin rash. Bacterial swabs were taken from the forehead of 17 cancer patients at baseline and at several time points after EGFRIs initiation, as well as from 20 healthy controls. The skin microbiome was analysed using 16S rRNA sequencing. The severity of the skin rash was assessed using the rash grade. Skin surface parameters (pH, water capacitance, and sebum level) were also measured. Compared with baseline, the abundance of Cutibacterium acnes decreased in 13 of 15 cases, and that of Staphylococcus aureus, Corynebacterium spp., Staphylococcus epidermidis or Proteobacteria increased in 13 of 15 cases after EGFRIs initiation. Skin pH increased significantly in parallel with a decrease in water capacitance after EGFRI initiation. Also, the composition of the skin microbiome of patients with severe rash was significantly different from that of healthy controls. In addition, the skin dysbiosis did not return to baseline during EGFRIs treatment for >1 year. These longitudinal observations indicate that skin dysbiosis is associated with development of skin rash.

    DOI: 10.1111/exd.14728

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  • Handling of Germline Findings in Clinical Comprehensive Cancer Genomic Profiling. Reviewed

    Mika Okazawa-Sakai, Yasuko Yamamoto, Mashu Futagawa, Miki Okamura, Satoko Miyawaki, Tomohiro Nishina, Kazuhiro Takehara, Toshiyuki Kozuki, Shuta Tomida, Ichinosuke Hyodo, Shozo Ohsumi, Akira Hirasawa

    Acta medica Okayama   76 ( 6 )   673 - 678   2022.12

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    Patients found to have presumed germline pathogenic variants (PGPVs) during comprehensive genomic profiling (CGP) require genetic counseling (GC) referrals. We retrospectively investigated the outcomes of patients with PGPVs. Among 159 patients who underwent CGP, we recommended GC for the 16 patients with PGPVs (3 with [FG group] and 13 without [G Group] a family/personal history of hereditary cancer) as well as for the 8 patients with no PGPVs, but a history (F group); 2 (67%), 5 (38%), and 3 (38%) patients received GC in the FG, G, and F groups, respectively. Germline testing results were positive in 1 and 2 patients of the FG and G groups, respectively. Among the patients recommended for GC, 58% did not receive GC due to lack of interest, poor performance status, or death. CGP contributes to the identification of germline variants in patients without a history of hereditary cancer. However, the proportion of patients who undergo GC should be improved.

    DOI: 10.18926/AMO/64117

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  • Establishment of a reference single-cell RNA sequencing dataset for human pancreatic adenocarcinoma Reviewed

    Ryota Chijimatsu, Shogo Kobayashi, Yu Takeda, Masatoshi Kitakaze, Shotaro Tatekawa, Yasuko Arao, Mika Nakayama, Naohiro Tachibana, Taku Saito, Daisuke Ennishi, Shuta Tomida, Kazuki Sasaki, Daisaku Yamada, Yoshito Tomimaru, Hidenori Takahashi, Daisuke Okuzaki, Daisuke Motooka, Takahito Ohshiro, Masateru Taniguchi, Yutaka Suzuki, Kazuhiko Ogawa, Masaki Mori, Yuichiro Doki, Hidetoshi Eguchi, Hideshi Ishii

    iScience   25 ( 8 )   104659 - 104659   2022.8

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    Single-cell RNA sequencing (scRNAseq) has been used to assess the intra-tumor heterogeneity and microenvironment of pancreatic ductal adenocarcinoma (PDAC). However, previous knowledge is not fully universalized. Here, we built a single cell atlas of PDAC from six datasets containing over 70 samples and >130,000 cells, and demonstrated its application to the reanalysis of the previous bulk transcriptomic cohorts and inferring cell–cell communications. The cell decomposition of bulk transcriptomics using scRNAseq data showed the cellular heterogeneity of PDAC; moreover, high levels of tumor cells and fibroblasts were indicative of poor-prognosis. Refined tumor subtypes signature indicated the tumor cell dynamics in intra-tumor and their specific regulatory network. We further identified functionally distinct tumor clusters that had close interaction with fibroblast subtypes via different signaling pathways dependent on subtypes. Our analysis provided a reference dataset for PDAC and showed its utility in research on the microenvironment of intra-tumor heterogeneity.

    DOI: 10.1016/j.isci.2022.104659

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  • Liquid Biopsy Revealed HBOC Pedigree and Led to Medical Management Among the Relatives.

    Chikako Ogawa, Akira Hirasawa, Reimi Sogawa, Kayoko Hasuoka, Shuta Tomida, Mashu Futagawa, Yusaku Urakawa, Mariko Kochi, Hideki Yamamoto, Keiichiro Nakamura, Hisashi Masuyama

    Acta medica Okayama   76 ( 4 )   479 - 483   2022.8

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    A hereditary breast and ovarian cancer (HBOC) pedigree was detected via liquid biopsy, and cancer prevention was initiated for the patient's daughter, after receiving a definitive result from BRCA genetic testing. A 48-yearold woman with ovarian cancer was administered precision medicine, which used cell-free DNA from plasma. The results revealed a pathogenic variant of BRCA1 as a presumed germline pathogenic mutation. We confirmed the germline pathological variant BRCA1 c.81-1G> A and suggested treatment with a PARP inhibitor. One of her three children had the variant, was diagnosed as an unaffected pathogenic variant carrier, and was advised to initiate surveillance.

    DOI: 10.18926/AMO/63908

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  • The Tumor Immune Microenvironment and Frameshift Neoantigen Load Determine Response to PD-L1 Blockade in Extensive-Stage SCLC. International journal

    Hiroaki Kanemura, Hidetoshi Hayashi, Shuta Tomida, Junko Tanizaki, Shinichiro Suzuki, Yusuke Kawanaka, Asuka Tsuya, Yasushi Fukuda, Hiroyasu Kaneda, Keita Kudo, Takayuki Takahama, Ryosuke Imai, Koji Haratani, Yasutaka Chiba, Tomoyuki Otani, Akihiko Ito, Kazuko Sakai, Kazuto Nishio, Kazuhiko Nakagawa

    JTO clinical and research reports   3 ( 8 )   100373 - 100373   2022.8

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    Introduction: Despite a considerable benefit of adding immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy for patients with extensive-stage SCLC (ES-SCLC), a durable response to ICIs occurs in only a small minority of such patients. Methods: A total of 135 patients with ES-SCLC treated with chemotherapy either alone (chemo-cohort, n = 71) or together with an ICI (ICI combo-cohort, n = 64) was included in this retrospective study. Tumors were classified pathologically as inflamed or noninflamed on the basis of programmed death-ligand 1 expression and CD8+ tumor-infiltrating lymphocyte density. Immune-related gene expression profiling was performed, and predicted neoantigen load was determined by whole-exome sequencing. Results: Among patients in the ICI combo-cohort, median progression-free survival was 10.8 and 5.1 months for those with inflamed (n = 7) or noninflamed (n = 56) tumors, respectively (log-rank test p = 0.002; hazard ratio of 0.26). Among the 89 patients with immune-related gene expression profiling data available, inflamed tumors had a higher T cell-inflamed GEP score than did noninflamed tumors (-0.18 versus -0.58, p < 0.001). The 12-month progression-free survival rate was 16.1% and 0% for patients in the ICI combo-cohort harboring tumors with a high (n = 26) or low (n = 18) frameshift neoantigen load, respectively. A high-frameshift neoantigen load was associated with up-regulation of gene signatures related to antigen presentation and costimulatory signaling. A durable clinical benefit of ICI therapy was observed only in patients with inflamed tumors and a high-frameshift neoantigen load. Conclusions: Expression of programmed death-ligand 1, CD8+ T cell infiltration, and a high-frameshift neoantigen load are associated with clinical benefit of ICI therapy in ES-SCLC. Clinical trial registration: UMIN000041056.

    DOI: 10.1016/j.jtocrr.2022.100373

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  • Drug repositioning of tranilast to sensitize a cancer therapy by targeting cancer-associated fibroblast. International journal

    Kosuke Ochi, Ken Suzawa, Yin Min Thu, Fumiaki Takatsu, Shimpei Tsudaka, Yidan Zhu, Kentaro Nakata, Tatsuaki Takeda, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Tadahiko Shien, Yoshiharu Okamoto, Shuta Tomida, Shinichi Toyooka

    Cancer science   113 ( 10 )   3428 - 3436   2022.7

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    Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment that mediate resistance of cancer cells to anticancer drugs. Tranilast is an antiallergic drug that suppresses the release of cytokines from various inflammatory cells. In this study, we investigated the inhibitory effect of tranilast on the interactions between non-small cell lung cancer (NSCLC) cells and the CAFs in the tumor microenvironment. Three EGFR-mutant NSCLC cell lines, two KRAS-mutant cell lines and three CAFs derived from NSCLC patients were used. To mimic the tumor microenvironment, the NSCLC cells were co-cultured with the CAFs in vitro, and the molecular profiles and sensitivity to molecular targeted therapy were assessed. Crosstalk between NSCLC cells and CAFs induced multiple biological effects on the NSCLC cells both in vivo and in vitro, including activation of the STAT3 signaling pathway, promotion of xenograft tumor growth, induction of epithelial-mesenchymal transition (EMT), and acquisition of resistance to molecular-targeted therapy, including of EGFR-mutant NSCLC cells to osimertinib and of KRAS-mutant NSCLC cells to selumetinib. Treatment with tranilast led to inhibition of IL-6 secretion from the CAFs, which, in turn, resulted in inhibition of CAF-induced phospho-STAT3 upregulation. Tranilast also inhibited CAF-induced EMT in the NSCLC cells. Finally, combined administration of tranilast with molecular-targeted therapy reversed the CAF-mediated resistance of the NSCLC cells to the molecular-targeted drugs, both in vitro and in vivo. Our results showed that combined administration of tranilast with molecular-targeted therapy is a possible new treatment strategy to overcome drug resistance caused by cancer- CAF interaction.

    DOI: 10.1111/cas.15502

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  • CD8+ T-cell responses are boosted by dual PD-1/VEGFR2 blockade after EGFR inhibition in Egfr-mutant lung cancer. Reviewed International journal

    Kazuya Nishii, Kadoaki Ohashi, Shuta Tomida, Takamasa Nakasuka, Atsuko Hirabae, Sachi Okawa, Jun Nishimura, Hisao Higo, Hiromi Watanabe, Hirohisa Kano, Chihiro Ando, Go Makimoto, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Heiichiro Udono, Yoshinobu Maeda, Katsuyuki Kiura

    Cancer immunology research   10 ( 9 )   1111 - 1126   2022.7

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    Epidermal growth factor receptor (EGFR) is the most frequently mutated driver oncogene in non-smoking-related, non-small-cell lung cancer (NSCLC). EGFR-mutant NSCLC has a non-inflamed tumor microenvironment (TME), with low infiltration by CD8+ T cells and, thus, immune checkpoint inhibitors, such as anti-programmed cell death-1 (anti-PD-1) have weak anti-tumor effects. Here, we showed that CD8+ T-cell responses were induced by an EGFR-tyrosine kinase inhibitor (TKI) in syngeneic Egfr-mutant NSCLC tumors, which was further pronounced by sequential dual blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2). However, simultaneous triple blockade had no such effect. PD-1/VEGFR2 dual blockade did not exert tumor-inhibitory effects without pre-treatment with the EGFR-TKI, suggesting that treatment schedule is crucial for efficacy of the dual blockade therapy. Pre-treatment with EGFR-TKI increased the CD8+ T-cell/regulatory T-cell (Treg) ratio, while also increasing expression of immunosuppressive chemokines and chemokine receptors, as well as increasing the number of M2-like macrophages, in the TME. Discontinuing EGFR-TKI treatment reversed the transient increase of immunosuppressive factors in the TME. The subsequent PD-1/VEGFR2 inhibition maintained increased numbers of infiltrating CD8+ T cells and CD11c+ dendritic cells. Depletion of CD8+ T cells in vivo abolished tumor growth inhibition by EGFR-TKI alone and the sequential triple therapy, suggesting that EGFR inhibition is a prerequisite for the induction of CD8+ T-cell responses. Our findings could aid in developing an alternative immunotherapy strategy in patients with cancers that have driver mutations and a non-inflamed TME.

    DOI: 10.1158/2326-6066.CIR-21-0751

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  • 学生発、がんゲノムゼミ。実臨床の経験を基にした自発的ゼミの立ち上げと報告

    宮崎 将司, 宇佐美 佳耶, 加藤 唯真, 川月 章弘, 木山 満就, 小堀 貴之, 増田 倫敦, 遠西 大輔, 冨田 秀太, 千々松 良太, 山下 範之, 豊岡 伸一

    医学教育   53 ( Suppl. )   223 - 223   2022.7

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    Language:Japanese   Publisher:(一社)日本医学教育学会  

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  • がん遺伝子パネル検査で検出されたPGPVの特性および遺伝子医療部門への介入方法の検討

    十川 麗美, 山本 英喜, 河内 麻里子, 二川 摩周, 加藤 芙美乃, 蓮岡 佳代子, 遠西 大輔, 冨田 秀太, 平沢 晃

    日本遺伝カウンセリング学会誌   43 ( 2 )   77 - 77   2022.6

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  • One-step nucleic acid amplification for intraoperative diagnosis of lymph node metastasis in lung cancer patients: a single-center prospective study. International journal

    Kei Namba, Ken Suzawa, Kazuhiko Shien, Akihiro Miura, Yuta Takahashi, Shunsaku Miyauchi, Kota Araki, Kentaro Nakata, Shuta Tomida, Shin Tanaka, Kentaroh Miyoshi, Shinji Otani, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Junichi Soh, Masaomi Yamane, Shinichi Toyooka

    Scientific reports   12 ( 1 )   7297 - 7297   2022.5

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    One-step nucleic acid amplification (OSNA) is a rapid intraoperative molecular detection technique for sentinel node assessment via the quantitative measurement of target cytokeratin 19 (CK19) mRNA to determine the presence of metastasis. It has been validated in breast cancer but its application in lung cancer has not been adequately investigated. 214 LNs from 105 patients with 100 primary lung cancers, 2 occult primary lung tumors, and 3 metastatic lung tumors, who underwent surgical lung resection with LN dissection between February 2018 and January 2020, were assessed. Resected LNs were divided into two parts: one was snap-frozen for OSNA and the other underwent rapidly frozen histological examination. Intraoperatively collected LNs were evaluated by OSNA using loop-mediated isothermal amplification and compared with intraoperative pathological diagnosis as a control. Among 214 LNs, 14 were detected as positive by OSNA, and 11 were positive by both OSNA and intraoperative pathological diagnosis. The sensitivity and specificity of OSNA was 84.6% and 98.5%, respectively. The results of 5 of 214 LNs were discordant, and the remainder all matched (11 positive and 198 negative) with a concordance rate of 97.7%. Although the analysis of public mRNA expression data from cBioPortal showed that CK19 expression varies greatly depending on the cancer type and histological subtype, the results of the five cases, except for primary lung cancer, were consistent. OSNA provides sufficient diagnostic accuracy and speed and can be applied to the intraoperative diagnosis of LN metastasis for non-small cell lung cancer.

    DOI: 10.1038/s41598-022-11064-4

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  • Identification of targetable kinases in idiopathic pulmonary fibrosis. International journal

    Hisao Higo, Kadoaki Ohashi, Shuta Tomida, Sachi Okawa, Hiromasa Yamamoto, Seiichiro Sugimoto, Satoru Senoo, Go Makimoto, Kiichiro Ninomiya, Takamasa Nakasuka, Kazuya Nishii, Akihiko Taniguchi, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Nobuaki Miyahara, Yoshinobu Maeda, Shinichi Toyooka, Katsuyuki Kiura

    Respiratory research   23 ( 1 )   20 - 20   2022.2

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    BACKGROUND: Tyrosine kinase activation plays an important role in the progression of pulmonary fibrosis. In this study, we analyzed the expression of 612 kinase-coding and cancer-related genes using next-generation sequencing to identify potential therapeutic targets for idiopathic pulmonary fibrosis (IPF). METHODS: Thirteen samples from five patients with IPF (Cases 1-5) and eight samples from four patients without IPF (control) were included in this study. Six of the thirteen samples were obtained from different lung segments of a single patient who underwent bilateral pneumonectomy. Gene expression analysis of IPF lung tissue samples (n = 13) and control samples (n = 8) was performed using SureSelect RNA Human Kinome Kit. The expression of the selected genes was further confirmed at the protein level by immunohistochemistry (IHC). RESULTS: Gene expression analysis revealed a correlation between the gene expression signatures and the degree of fibrosis, as assessed by Ashcroft score. In addition, the expression analysis indicated a stronger heterogeneity among the IPF lung samples than among the control lung samples. In the integrated analysis of the 21 samples, DCLK1 and STK33 were found to be upregulated in IPF lung samples compared to control lung samples. However, the top most upregulated genes were distinct in individual cases. DCLK1, PDK4, and ERBB4 were upregulated in IPF case 1, whereas STK33, PIM2, and SYK were upregulated in IPF case 2. IHC revealed that these proteins were expressed in the epithelial layer of the fibrotic lesions. CONCLUSIONS: We performed a comprehensive kinase expression analysis to explore the potential therapeutic targets for IPF. We found that DCLK1 and STK33 may serve as potential candidate targets for molecular targeted therapy of IPF. In addition, PDK4, ERBB4, PIM2, and SYK might also serve as personalized therapeutic targets of IPF. Additional large-scale studies are warranted to develop personalized therapies for patients with IPF.

    DOI: 10.1186/s12931-022-01940-y

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  • 基礎からわかるゲノム医療 がんゲノム医療と肺がん

    豊岡 伸一, 蓮岡 佳代子, 久保 寿夫, 遠西 大輔, 冨田 秀太

    肺癌   61 ( 6 )   522 - 522   2021.10

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  • 包括的ゲノムプロファイリングを用いた神経内分泌癌の治療探索と生殖細胞系列の推定

    山本 英喜, 河内 麻里子, 堀口 繁, 榮 浩行, 久保 寿夫, 二宮 貴一朗, 西森 久和, 高本 篤, 遠西 大輔, 冨田 秀太, 宮本 理史, 田端 雅弘, 柳井 広之, 豊岡 伸一, 平沢 晃

    日本癌治療学会学術集会抄録集   59回   O73 - 3   2021.10

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  • 消化器領域細胞診への細胞検査士の挑戦 胆・膵癌におけるがん遺伝子パネル検査の課題 細胞診にできること

    井上 博文, 松岡 博美, 實平 悦子, 松岡 昌志, 冨田 秀太, 松本 和幸, 堀口 繁, 加藤 博也, 山本 英喜, 柳井 広之, 平沢 晃

    日本臨床細胞学会雑誌   60 ( Suppl.2 )   470 - 470   2021.10

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  • 小細胞癌のICI(Treatment of SCLC) 進展型小細胞肺癌における腫瘍微小免疫環境の網羅的解析

    金村 宙昌, 林 秀敏, 大谷 知之, 冨田 秀太, 鈴木 慎一郎, 原谷 浩司, 谷崎 潤子, 津谷 あす香, 福田 泰, 金田 裕靖, 工藤 慶太, 高濱 隆幸, 今井 亮介, 千葉 康敬, 西尾 和人, 伊藤 彰彦, 中川 和彦

    肺癌   61 ( 6 )   499 - 499   2021.10

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  • CEBPγ facilitates lamellipodia formation and cancer cell migration through CERS6 upregulation. International journal

    Hanxiao Shi, Atsuko Niimi, Toshiyuki Takeuchi, Kazuya Shiogama, Yasuyoshi Mizutani, Taisuke Kajino, Kenichi Inada, Tetsunari Hase, Takahiro Hatta, Hirofumi Shibata, Takayuki Fukui, Toyofumi Fengshi Chen-Yoshikawa, Kazuki Nagano, Takashi Murate, Yoshiyuki Kawamoto, Shuta Tomida, Takashi Takahashi, Motoshi Suzuki

    Cancer science   112 ( 7 )   2770 - 2780   2021.7

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    Ceramide synthase 6 (CERS6) promotes lung cancer metastasis by stimulating cancer cell migration. To examine the underlying mechanisms, we performed luciferase analysis of the CERS6 promoter region and identified the Y-box as a cis-acting element. As a parallel analysis of database records for 149 non-small-cell lung cancer (NSCLC) cancer patients, we screened for trans-acting factors with an expression level showing a correlation with CERS6 expression. Among the candidates noted, silencing of either CCAAT enhancer-binding protein γ (CEBPγ) or Y-box binding protein 1 (YBX1) reduced the CERS6 expression level. Following knockdown, CEBPγ and YBX1 were found to be independently associated with reductions in ceramide-dependent lamellipodia formation as well as migration activity, while only CEBPγ may have induced CERS6 expression through specific binding to the Y-box. The mRNA expression levels of CERS6, CEBPγ, and YBX1 were positively correlated with adenocarcinoma invasiveness. YBX1 expression was observed in all 20 examined clinical lung cancer specimens, while 6 of those showed a staining pattern similar to that of CERS6. The present findings suggest promotion of lung cancer migration by possible involvement of the transcription factors CEBPγ and YBX1.

    DOI: 10.1111/cas.14928

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  • Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression. International journal

    Makoto Nakamura, Yusuke Meguri, Shuntaro Ikegawa, Takumi Kondo, Yuichi Sumii, Takuya Fukumi, Miki Iwamoto, Yasuhisa Sando, Hiroyuki Sugiura, Noboru Asada, Daisuke Ennishi, Shuta Tomida, Emi Fukuda-Kawaguchi, Yasuyuki Ishii, Yoshinobu Maeda, Ken-Ichi Matsuoka

    Scientific reports   11 ( 1 )   13125 - 13125   2021.6

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    Posttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient's condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by α-galactosylceramide (α-GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of α-GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4+Foxp3+ regulatory T cells. These studies indicate that α-GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk.

    DOI: 10.1038/s41598-021-92526-z

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  • Oncogenic potential of human pluripotent stem cell-derived lung organoids with HER2 overexpression. International journal

    Akihiro Miura, Daisuke Yamada, Masahiro Nakamura, Shuta Tomida, Dai Shimizu, Yan Jiang, Tomoka Takao, Hiromasa Yamamoto, Ken Suzawa, Kazuhiko Shien, Masaomi Yamane, Masakiyo Sakaguchi, Shinichi Toyooka, Takeshi Takarada

    International journal of cancer   149 ( 8 )   1593 - 1604   2021.6

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    Lung adenocarcinoma (LUAD) is the most common types among lung cancers generally arising from terminal airway and understanding of multistep carcinogenesis is crucial to develop novel therapeutic strategy for LUAD. Here we used human induced pluripotent stem cells (hiPSCs) to establish iHER2-hiPSCs in which doxycycline induced the expression of the oncoprotein human epidermal growth factor receptor 2 (HER2)/ERBB2. Lung progenitors that differentiated from iHER2-hiPSCs, which expressed NKX2-1/TTF-1 known as a lung lineage maker, were cocultured with human fetal fibroblast and formed human lung organoids (HLOs) comprising alveolar type 2-like cells. HLOs that overexpressed HER2 transformed to tumor-like structures similar to atypical adenomatous hyperplasia, which is known for lung precancerous lesion and upregulated the activities of oncogenic signaling cascades such as RAS/RAF/MAPK and PI3K/AKT/mTOR. The degree of morphological irregularity and proliferation capacity were significantly higher in HLOs from iHER2-hiPSCs. Moreover, the transcriptome profile of the HLOs shifted from a normal lung tissue-like state to one characteristic of clinical LUAD with HER2 amplification. Our results suggest that hiPSC-derived HLOs may serve as a model to recapitulate the early tumorigenesis of LUAD and would provide new insights into the molecular basis of tumor initiation and progression.

    DOI: 10.1002/ijc.33713

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  • Best practices for the extraction of genomic DNA from formalin-fixed paraffin-embedded tumor tissue for cancer genomic profiling tests. Reviewed International journal

    Hirofumi Inoue, Shuta Tomida, Shigeru Horiguchi, Hironari Kato, Hiromi Matsuoka, Etsuko Sanehira, Masashi Matsuoka, Hiroyuki Yanai, Akira Hirasawa, Shinichi Toyooka

    Pathology international   71 ( 5 )   360 - 364   2021.5

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    Recently, two cancer genomic profiling tests have been approved in Japan and implemented in routine clinical practice: the FDA-approved FoundationOne CDx test, and the OncoGuide NCC Oncopanel test. The quality and quantity of DNA significantly affects the sequencing results; therefore, preparing a sufficient amount of high-quality DNA for clinical cancer genomic profiling tests is important. We examined the best practices for the extraction of cancer genomic DNA from formalin-fixed paraffin-embedded (FFPE) tumor tissues of pancreatic, lung and colon cancer specimens. We found that the quality of cancer genomic DNA extracted from 10-μm-thick FFPE samples improved significantly, compared with that from 4-μm-thick FFPE samples, suggesting that 10-μm-thick FFPE samples are preferable for clinical cancer genomic profiling tests. For convenience, we created a quick reference table for calculating the required number of FFPE slides.

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  • 【骨・軟部腫瘍のマネジメント(その1)】診断 組織・遺伝子診断 肉腫におけるがんゲノム医療の意義

    中田 英二, 藤原 智洋, 国定 俊之, 尾崎 敏文, 遠西 大輔, 冨田 秀太, 平沢 晃, 二川 摩周, 武田 達明

    別冊整形外科   ( 79 )   75 - 83   2021.4

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    <文献概要>はじめに がんにはさまざまな遺伝子異常を認め,同一のがん種でも発現する遺伝子が異なることが少なくない.最近,次世代シークエンサー(next generation sequencer:NGS)を用いて遺伝子異常を同時多重性(マルチプレックス)に検出するがん遺伝子パネルが登場した.がんゲノム医療では,がん遺伝子パネルで同定した遺伝子変異に基づいて薬剤を選択する,精密医療(precision medicine)が行われる.本稿では,肉腫におけるゲノム医療の意義について述べる.

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  • Microbiome composition comparison in oral and atherosclerotic plaque from patients with and without periodontitis.

    Daichi Isoshima, Keisuke Yamashiro, Kazuyuki Matsunaga, Makoto Taniguchi, Takehiro Matsubara, Shuta Tomida, Shinzo Ota, Michiyoshi Sato, Yutaka Shimoe, Tatsuo Kohriyama, Zulema Arias, Kazuhiro Omori, Tadashi Yamamoto, Shogo Takashiba

    Odontology   109 ( 1 )   239 - 249   2021.1

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    There is no conclusive evidence regarding a causal relationship between periodontitis and atherosclerosis. In this study, we examined the microbiome in the oral cavity and atheromatous plaques from atherosclerosis patients with or without periodontitis to investigate the role of oral bacteria in the formation of atheromatous plaques. We chose four patients with and without periodontitis, who had undergone carotid endarterectomy. Bacterial samples were extracted from the tongue surface, from periodontal pocket (during the oral examination), and from the atheromatous plaques (APs). We investigated the general and oral conditions from each patient and performed next-generation sequencing (NGS) analysis for all bacterial samples. There were no significant differences between both groups concerning general conditions. However, the microbiome patterns of the gingival pocket showed differences depending on the absence or presence of periodontitis, while those of the tongue surface were relatively similar. The microbiome pattern of the atheromatous plaques was entirely different from that on the tongue surface and gingival pocket, and oral bacteria were seldom detected. However, the microbiome pattern in atheromatous plaques was different in the presence or absence of periodontitis. These results suggested that oral bacteria did not affect the formation of atheromatous plaques directly.

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  • The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis. International journal

    Kota Araki, Rie Kinoshita, Nahoko Tomonobu, Yuma Gohara, Shuta Tomida, Yuta Takahashi, Satoru Senoo, Akihiko Taniguchi, Junko Itano, Ken-Ichi Yamamoto, Hitoshi Murata, Ken Suzawa, Kazuhiko Shien, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Kouichi Ichimura, Masahiro Nishibori, Nobuaki Miyahara, Shinichi Toyooka, Masakiyo Sakaguchi

    Journal of molecular medicine (Berlin, Germany)   99 ( 1 )   131 - 145   2021.1

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    In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts' differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia. HIGHLIGHTS: S100A8/A9 level is highly upregulated in the IPF patients' lungs as well as the blood. S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts. The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts. The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model. In idiopathic pulmonary fibrosis (IPF), S100A8/A9, a heterodimer composed of S100A8 and S100A9 proteins, plays a crucial role in the onset of inflammation and the subsequent formation of a feed-forward inflammatory loop that promotes fibrosis. (1) The local, pronounced increase in S100A8/A9 in the injured inflammatory lung region-which is provided mainly by the activated neutrophils and macrophages-exerts strong inflammatory signals accompanied by dozens of inflammatory soluble factors including cytokines, chemokines, and growth factors that further act to produce and secrete S100A8/A9, eventually making a sustainable inflammatory circuit that supplies an indefinite presence of S100A8/A9 in the extracellular space with a mal-increased level. (2) The elevated S100A8/A9 compels fibroblasts to activate through receptor for advanced glycation end products (RAGE), one of the major S100A8/A9 receptors, resulting in the activation of NFκB, leading to fibroblast mal-events (e.g., elevated cell proliferation and transdifferentiation to myofibroblasts) that actively produce not only inflammatory cytokines but also collagen matrices. (3) Finally, the S100A8/A9-derived activation of lung fibroblasts under a chronic inflammation state leads to fibrosis events and constantly worsens fibrosis in the lung. Taken together, these findings suggest that the extracellular S100A8/A9 heterodimer protein is a novel mainstay soluble factor for IPF that exerts many functions as described above (1-3). Against this background, we herein applied the developed S100A8/A9 neutralizing antibody to prevent IPF. The IPF imitating lung fibrosis in an IPF mouse model was effectively blocked by treatment with the antibody, leading to enhanced survival. The developed S100A8/A9 antibody, as an innovative novel biologic, may help shed light on the difficulties encountered with IPF therapy in clinical settings.

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  • Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial. International journal

    Hidetoshi Hayashi, Yuichi Takiguchi, Hironobu Minami, Kohei Akiyoshi, Yoshihiko Segawa, Hiroki Ueda, Yasuo Iwamoto, Chihiro Kondoh, Koji Matsumoto, Shin Takahashi, Hisateru Yasui, Toshiyuki Sawa, Yusuke Onozawa, Yasutaka Chiba, Yosuke Togashi, Yoshihiko Fujita, Kazuko Sakai, Shuta Tomida, Kazuto Nishio, Kazuhiko Nakagawa

    JAMA oncology   6 ( 12 )   1931 - 1938   2020.12

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    Importance: Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach. Objective: To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP. Design, Setting, and Participants: This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan. Interventions: RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations. Main Outcomes And Measures: The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations. Results: Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months. Conclusions and Relevance: This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP. Trial Registration: UMIN Identifier: UMIN000016794.

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  • Detection of epidermal growth factor receptor mutations in exhaled breath condensate using droplet digital polymerase chain reaction. International journal

    Kazuya Nishii, Kadoaki Ohashi, Tomoki Tamura, Kiichiro Ninomiya, Takehiro Matsubara, Satoru Senoo, Hirohisa Kano, Hiromi Watanabe, Naohiro Oda, Go Makimoto, Hisao Higo, Yuka Kato, Takashi Ninomiya, Toshio Kubo, Hiromasa Yamamoto, Shuta Tomida, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Yoshinobu Maeda, Katsuyuki Kiura

    Oncology letters   20 ( 6 )   393 - 393   2020.12

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    The detection of certain oncogenic driver mutations, including those of epidermal growth factor receptor (EGFR), is essential for determining treatment strategies for advanced non-small cell lung cancer (NSCLC). The current study assessed the feasibility of testing exhaled breath condensate (EBC) for EGFR mutations by droplet digital PCR (ddPCR). Samples were collected from 12 patients with NSCLC harboring EGFR mutations that were admitted to Okayama University Hospital between June 1, 2014 and December 31, 2017. A total of 21 EBC samples were collected using the RTube™ method and EGFR mutations (L858R, exon 19 deletions or T790M) were assessed through ddPCR analysis (EBC-ddPCR). A total of 3 healthy volunteer samples were also tested to determine a threshold value for each mutation. Various patient characteristics were determined, including sex (3 males and 9 females), age (range 54-81 years; median, 66 years), smoking history (10 had never smoked; 2 were former smokers), histology (12 patients exhibited adenocarcinoma), clinical stage (9 patients were stage IV; 3 exhibited post-operative recurrence) and EGFR mutation type (4 had L858R; 8 had exon 19 deletions; 8 had T790M). EBC-ddPCR demonstrated positive droplets in 8 of the 12 patients. The sensitivity and specificity of each mutation was as follows: 27.3 and 80.0% for EGFR L858R, 30.0 and 90.9% for EGFR Ex19del, and 22.2 and 100% for EGFR T790M. EBC-ddPCR analysis of EGFR mutations exhibited modest sensitivity and acceptable specificity. EBC-ddPCR is a minimally invasive and replicable procedure and may be a complementary method for EGFR testing in patients where blood or tissue sampling proves difficult.

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  • 最新版!ゲノム診断における細胞診【春秋シリーズ】がんゲノム医療に順応する細胞診検査体制 Rapid on-site evaluation:ROSEへの対応

    井上 博文, 松岡 博美, 實平 悦子, 松岡 昌志, 冨田 秀太, 平沢 晃, 柳井 広之

    日本臨床細胞学会雑誌   59 ( Suppl.2 )   480 - 480   2020.11

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  • Diameter Is a Key 3D Characteristic for Assessments of Efficient Inhibitors of Protein-Protein Interactions. Reviewed International journal

    Masakazu Nakadai, Shuta Tomida

    Journal of chemical information and modeling   60 ( 10 )   4785 - 4790   2020.10

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    Three-dimensional (3D) molecular descriptors, including physicochemical and shape properties, for protein-protein interaction (PPI) interface inhibitors have become a topic of discussion. However, the relationships between such properties and binding free energy have not been adequately investigated. In this study, we focused on identifying key 3D molecular descriptors related to the binding free energy and/or the ligand efficiency (LE) of PPI interface inhibitors. A positive correlation was found between the binding free energy and the diameter (D) of cylindrical 3D molecules, in addition to a correlation between LE and D/heavy atom count (HAC). In addition, we showed a correlation between LE and D/HAC for macrocyclic compounds, suggesting that the present findings could be applied during assessments of the potential of macrocyclic PPI interface inhibitors in drug discovery processes.

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  • CERS6 required for cell migration and metastasis in lung cancer. International journal

    Motoshi Suzuki, Ke Cao, Seiichi Kato, Naoki Mizutani, Kouji Tanaka, Chinatsu Arima, Mei Chee Tai, Norie Nakatani, Kiyoshi Yanagisawa, Toshiyuki Takeuchi, Hanxiao Shi, Yasuyoshi Mizutani, Atsuko Niimi, Tetsuo Taniguchi, Takayuki Fukui, Kohei Yokoi, Keiko Wakahara, Yoshinori Hasegawa, Yukiko Mizutani, Soichiro Iwaki, Satoshi Fujii, Akira Satou, Keiko Tamiya-Koizumi, Takashi Murate, Mamoru Kyogashima, Shuta Tomida, Takashi Takahashi

    Journal of cellular and molecular medicine   24 ( 20 )   11949 - 11959   2020.10

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    Sphingolipids constitute a class of bio-reactive molecules that transmit signals and exhibit a variety of physical properties in various cell types, though their functions in cancer pathogenesis have yet to be elucidated. Analyses of gene expression profiles of clinical specimens and a panel of cell lines revealed that the ceramide synthase gene CERS6 was overexpressed in non-small-cell lung cancer (NSCLC) tissues, while elevated expression was shown to be associated with poor prognosis and lymph node metastasis. NSCLC profile and in vitro luciferase analysis results suggested that CERS6 overexpression is promoted, at least in part, by reduced miR-101 expression. Under a reduced CERS6 expression condition, the ceramide profile became altered, which was determined to be associated with decreased cell migration and invasion activities in vitro. Furthermore, CERS6 knockdown suppressed RAC1-positive lamellipodia/ruffling formation and attenuated lung metastasis efficiency in mice, while forced expression of CERS6 resulted in an opposite phenotype in examined cell lines. Based on these findings, we consider that ceramide synthesis by CERS6 has important roles in lung cancer migration and metastasis.

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  • 遺伝性腫瘍-最新情報と今後の方向性 がん遺伝子パネル検査によるがん個別化医療と遺伝性腫瘍への実効果

    山本 英喜, 久保 寿夫, 冨田 秀太, 遠西 大輔, 豊岡 伸一, 平沢 晃

    日本癌学会総会記事   79回   S21 - 5   2020.10

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  • Overcoming epithelial-mesenchymal transition-mediated drug resistance with monensin-based combined therapy in non-small cell lung cancer. Reviewed International journal

    Kosuke Ochi, Ken Suzawa, Shuta Tomida, Kazuhiko Shien, Jui Takano, Shunsaku Miyauchi, Tatsuaki Takeda, Akihiro Miura, Kota Araki, Kentaro Nakata, Hiromasa Yamamoto, Mikio Okazaki, Seiichiro Sugimoto, Tadahiko Shien, Masaomi Yamane, Kazuo Azuma, Yoshiharu Okamoto, Shinichi Toyooka

    Biochemical and biophysical research communications   529 ( 3 )   760 - 765   2020.8

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    BACKGROUND: The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors. MATERIALS AND METHODS: A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-β-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed. RESULTS: TGF-β treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-β-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-β-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor. CONCLUSION: Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance.

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  • Antitumor Effects of Pan-RAF Inhibitor LY3009120 Against Lung Cancer Cells Harboring Oncogenic BRAF Mutation. Reviewed International journal

    Shunsaku Miyauchi, Kazuhiko Shien, Tatsuaki Takeda, Kota Araki, Kentaro Nakata, Akihiro Miura, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Ken Suzawa, Hiromasa Yamamoto, Mikio Okazaki, Junichi Soh, Shuta Tomida, Masaomi Yamane, Masakiyo Sakaguchi, Shinichi Toyooka

    Anticancer research   40 ( 5 )   2667 - 2673   2020.5

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    BACKGROUND/AIM: The therapeutic strategy for patients with non-small-cell lung cancer (NSCLC) harboring the BRAF non-V600E mutation has not been established. LY3009120, a newly discovered pan-RAF inhibitor, has shown strong antitumor effects in cancers with various BRAF genotypes. This study investigated the antitumor effects of LY3009120 in NSCLC cells harboring the BRAF non-V600E mutation. MATERIALS AND METHODS: We examined the antitumor effects of LY3009120 by MTS assay and flow cytometry. We analyzed the expression status of proteins by western blot. The mouse xenograft models were used for the in vivo experiments. RESULTS: LY3009120 suppressed BRAF-related downstream pathway molecules and induced cleavage of poly ADP-ribose polymerase in all examined NSCLC cell lines. LY3009120 also inhibited in vivo tumor growth in NSCLC cells harboring the BRAF non-V600E mutation. CONCLUSION: LY3009120 is a potent therapeutic agent for patients with BRAF non-V600E mutant NSCLC.

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  • チームアプローチで実現するゲノム医療と薬剤師の役割 ゲノム医療におけるデータサイエンティストの役割と育成

    冨田 秀太, 森田 瑞樹, 山下 範之, 平沢 晃, 豊岡 伸一

    薬学雑誌   140 ( 5 )   657 - 661   2020.5

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    次世代シークエンサーを用いた遺伝子パネル検査とそのデータ解析はゲノム医療の根幹であるにもかかわらず、その担い手であるデータサイエンティストが極端に不足している。基本的なデータ解析の流れを理解し、解析結果の解釈ができる人材育成が喫緊の課題である。遺伝子パネル検査の流れを概説するとともに、遺伝子変異量(TMB)の概念と遺伝子パネル検査におけるTMBの算出方法について解説した。

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  • EGFRチロシンキナーゼ阻害薬のEGFR遺伝子変異陽性進行非小細胞肺癌の腫瘍微小環境への影響

    磯本 晃佑, 原谷 浩司, 林 秀敏, 加藤 了資, 田中 薫, 武田 真幸, 中川 和彦, 清水 重喜, 伊藤 彰彦, 冨田 秀太, 丹羽 崇, 小倉 高志, 横山 俊秀, 福田 泰, 石田 直, 千葉 康敬, 谷崎 潤子

    肺癌   60 ( 2 )   149 - 149   2020.4

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  • DV200 Index for Assessing RNA Integrity in Next-Generation Sequencing. Reviewed International journal

    Takehiro Matsubara, Junichi Soh, Mizuki Morita, Takahiro Uwabo, Shuta Tomida, Toshiyoshi Fujiwara, Susumu Kanazawa, Shinichi Toyooka, Akira Hirasawa

    BioMed research international   2020   9349132 - 9349132   2020

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    Poor quality of biological samples will result in an inaccurate analysis of next-generation sequencing (NGS). Therefore, methods to accurately evaluate sample integrity are needed. Among methods for evaluating RNA quality, the RNA integrity number equivalent (RINe) is widely used, whereas the DV200, which evaluates the percentage of fragments of >200 nucleotides, is also used as a quality assessment standard. In this study, we compared the RINe and DV200 RNA quality indexes to determine the most suitable RNA index for the NGS analysis. Seventy-one RNA samples were extracted from formalin-fixed paraffin-embedded tissue samples (n = 30), fresh-frozen samples (n = 25), or cell lines (n = 16). After assessing RNA quality using the RINe and DV200, we prepared two kinds of stranded mRNA sequencing libraries. Finally, we calculated the correlation between each RNA quality index and the amount of library product (1st PCR product per input RNA). The DV200 measure showed stronger correlation with the amount of library product than the RINe (R 2 = 0.8208 for the DV200 versus 0.6927 for the RINe). Receiver operating characteristic curve analyses revealed that the DV200 was the better marker for predicting efficient library production than the RINe using a threshold of >10 ng/ng for the amount of the 1st PCR product per input RNA (cutoff value for the RINe and DV200, 2.3 and 66.1%; area under the curve, 0.99 and 0.91; sensitivity, 82% and 92%; and specificity, 93% and 100%, respectively). Our results indicate that NGS libraries prepared using RNA samples with the DV200 value > 66.1% exhibit greater sensitivity and specificity than those prepared with the RINe values > 2.3. These findings suggest that the DV200 is superior to the RINe, especially for low-quality RNA, because it is a more consistent assessment of the amount of the 1st NGS library product per input.

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  • [Training Medical Staff with Basic Skills for Data Science in Genomic Medicine].

    Shuta Tomida, Mizuki Morita, Noriyuki Yamashita, Akira Hirasawa, Shinichi Toyooka

    Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan   140 ( 5 )   657 - 661   2020

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    The development of specialized training programs for medical personnel, particularly nurses, clinical laboratory technicians, and pharmacists, is considered critical for the promotion of genomic medicine throughout Japan. Specifically, medical personnel skilled at analyzing and understanding high-throughput genomic data are in high demand. In this symposium, we will introduce the basic knowledge and skills necessary for processing genomic data.

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  • YES1 activation induces acquired resistance to neratinib in HER2-amplified breast and lung cancers. Reviewed

    Takeda T, Yamamoto H, Suzawa K, Tomida S, Miyauchi S, Araki K, Nakata K, Miura A, Namba K, Shien K, Soh J, Shien T, Kitamura Y, Sendo T, Toyooka S

    Cancer science   111 ( 3 )   849 - 856   2019.12

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    Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.

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  • 臨床的疑問より発した研究-Reverse translational research High tumor mutation burdenのALK陽性肺癌におけるアレクチニブ早期耐性について

    槇本 剛, 大橋 圭明, 冨田 秀太, 二宮 貴一朗, 久保 寿夫, 頼 冠名, 市原 英基, 堀田 勝幸, 田端 雅弘, 豊岡 伸一, 木浦 勝行

    肺癌   59 ( 6 )   571 - 571   2019.11

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  • 腫瘍免疫と微小環境 EGFRチロシンキナーゼ阻害薬のEGFR遺伝子変異陽性進行非小細胞肺癌の腫瘍微小環境への影響

    磯本 晃佑, 原谷 浩司, 林 秀敏, 清水 重喜, 富田 秀太, 丹羽 崇, 横山 俊秀, 福田 泰, 千葉 康敬, 加藤 了資, 谷崎 潤子, 田中 薫, 武田 真幸, 小倉 高志, 石田 直, 伊藤 彰彦, 中川 和彦

    肺癌   59 ( 6 )   567 - 567   2019.11

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  • バイオバンクでの長期保存生体試料の品質管理標準化のための予備的検討

    山本 英喜, 松原 岳大, 森田 瑞樹, 冨田 秀太, 豊岡 伸一, 平沢 晃

    臨床病理   67 ( 補冊 )   283 - 283   2019.10

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  • Clinical and immune profiling for cancer of unknown primary site. Reviewed

    Haratani K, Hayashi H, Takahama T, Nakamura Y, Tomida S, Yoshida T, Chiba Y, Sawada T, Sakai K, Fujita Y, Togashi Y, Tanizaki J, Kawakami H, Ito A, Nishio K, Nakagawa K

    Journal for immunotherapy of cancer   7 ( 1 )   251   2019.9

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    DOI: 10.1186/s40425-019-0720-z

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    Other Link: http://link.springer.com/article/10.1186/s40425-019-0720-z/fulltext.html

  • 非小細胞肺癌におけるモネンシン併用療法によるEMT関連薬剤耐性の克服(Overcoming EMT-mediated drug resistance with Monensin-based combined therapy in non-small cell lung cancer)

    大智 宏祐, 諏澤 憲, 冨田 秀太, 荒木 恒太, 宮内 俊策, 三浦 章博, 武田 達明, 難波 圭, 枝園 和彦, 山本 寛斉, 岡崎 幹生, 枝園 忠彦, 豊岡 伸一

    日本癌学会総会記事   78回   P - 1139   2019.9

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  • 転移がんに有効なS100A8/A9阻害薬の開発(Novel therapeutic approach based on S100A8/A9-mediated organ tropic cancer metastasis)

    木下 理恵, 友信 奈保子, 山内 明, 枝園 和彦, 冨田 秀太, 村田 等, 二見 淳一郎, 近藤 英作, 豊岡 伸一, 阪口 政清

    日本癌学会総会記事   78回   P - 2252   2019.9

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  • EGFRチロシンキナーゼ阻害薬のEGFR遺伝子変異陽性進行非小細胞肺癌のPD-L1発現率への影響

    磯本 晃佑, 原谷 浩司, 林 秀敏, 清水 重喜, 冨田 秀太, 丹羽 崇, 横山 俊秀, 福田 泰, 千葉 康敬, 加藤 了資, 谷崎 潤子, 田中 薫, 武田 真幸, 小倉 高志, 石田 直, 伊藤 彰彦, 中川 和彦

    肺癌   59 ( 4 )   419 - 419   2019.8

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  • 病理コンパニオン診断と細胞診 がんゲノム医療を考慮した病理検体取扱いについて

    井上 博文, 冨田 秀太, 山本 英喜, 柳井 広之, 平沢 晃

    日本臨床細胞学会中国四国連合会会報   ( 34 )   15 - 15   2019.7

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  • Proposal of new combination, Cutibacterium acnes subsp. elongatum comb. nov., and emended descriptions of the genus Cutibacterium, Cutibacterium acnes subsp. acnes and Cutibacterium acnes subsp. defendens. Reviewed

    Dekio I, McDowell A, Sakamoto M, Tomida S, Ohkuma M

    International journal of systematic and evolutionary microbiology   69 ( 4 )   1087 - 1092   2019.4

  • EGFR-TKI耐性NSCLCに対するHSP90阻害剤ganetespibの有用性の検討

    栗原 英祐, 枝園 和彦, 鳥越 英次郎, 武田 達明, 荒木 恒太, 宮内 俊策, 三浦 章博, 高橋 優太, 諏澤 憲, 山本 寛斉, 宗 淳一, 冨田 秀太, 豊岡 伸一

    日本呼吸器外科学会雑誌   33 ( 3 )   O17 - 4   2019.4

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  • チームアプローチで実現するゲノム医療と薬剤師の役割 ゲノム医療におけるデータサイエンティストの役割と育成

    冨田 秀太, 森田 瑞樹, 山下 範之, 平沢 晃, 豊岡 伸一

    日本薬学会年会要旨集   139年会 ( 1 )   264 - 264   2019.3

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  • Application of amplicon-based targeted sequencing with the molecular barcoding system to detect uncommon minor EGFR mutations in patients with treatment-naïve lung adenocarcinoma. Reviewed International journal

    Kei Namba, Shuta Tomida, Takehiro Matsubara, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Takahiro Yoshioka, Tatsuaki Takeda, Hidejiro Torigoe, Hiroki Sato, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Kazunori Tsukuda, Shinichi Toyooka

    BMC cancer   19 ( 1 )   175 - 175   2019.2

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    BACKGROUND: In lung cancer, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor sensitizing mutations co-existing with rare minor EGFR mutations are known as compound mutations. These minor EGFR mutations can lead to acquired resistance after EGFR tyrosine kinase inhibitor treatment, so determining the mutation status of patients is important. However, using amplicon-based targeted deep sequencing based on next-generation sequencing to characterize mutations is prone to sequencing error. We therefore assessed the benefit of incorporating molecular barcoding with high-throughput sequencing to investigate genomic heterogeneity in treatment-naïve patients who have undergone resection of their non-small cell lung cancer (NSCLC) EGFR mutations. METHODS: We performed amplicon-based targeted sequencing with the molecular barcoding system (MBS) to detect major common EGFR mutations and uncommon minor mutations at a 0.5% allele frequency in fresh-frozen lung cancer samples. RESULTS: Profiles of the common mutations of EGFR identified by MBS corresponded with the results of clinical testing in 63 (98.4%) out of 64 cases. Uncommon mutations of EGFR were detected in seven cases (10.9%). Among the three types of major EGFR mutations, patients with the G719X mutation had a significantly higher incidence of compound mutations than those with the L858R mutation or exon 19 deletion (p = 0.0052). This was validated in an independent cohort from the Cancer Genome Atlas dataset (p = 0.018). CONCLUSIONS: Our findings demonstrate the feasibility of using the MBS to establish an accurate NSCLC patient genotype. This work will help understand the molecular basis of EGFR compound mutations in NSCLC, and could aid the development of new treatment modalities.

    DOI: 10.1186/s12885-019-5374-1

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  • Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment in EGFR-Mutant Non-Small Cell Lung Cancer Cells. Reviewed International journal

    Kei Namba, Kazuhiko Shien, Yuta Takahashi, Hidejiro Torigoe, Hiroki Sato, Takahiro Yoshioka, Tatsuaki Takeda, Eisuke Kurihara, Yusuke Ogoshi, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Shinichi Toyooka

    Molecular cancer research : MCR   17 ( 2 )   499 - 507   2019.2

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    Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistant cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multigene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib. IMPLICATIONS: Upregulation of AXL is one of the mechanisms of acquired resistance to osimertinib, and combination of osimertinib and cabozantinib might be a key treatment for overcoming osimertinib resistance.

    DOI: 10.1158/1541-7786.MCR-18-0628

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  • MET or NRAS amplification is an acquired resistance mechanism to the third-generation EGFR inhibitor naquotinib Reviewed

    Kiichiro Ninomiya, Kadoaki Ohashi, Go Makimoto, Shuta Tomida, Hisao Higo, Hiroe Kayatani, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

    Scientific Reports   8 ( 1 )   1955   2018.12

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    As a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimeritnib is the standard treatment for patients with non-small cell lung cancer harboring the EGFR T790M mutation
    however, acquired resistance inevitably develops. Therefore, a next-generation treatment strategy is warranted in the osimertinib era. We investigated the mechanism of resistance to a novel EGFR-TKI, naquotinib, with the goal of developing a novel treatment strategy. We established multiple naquotinib-resistant cell lines or osimertinib-resistant cells, two of which were derived from EGFR-TKI-naïve cells
    the others were derived from gefitinib- or afatinib-resistant cells harboring EGFR T790M. We comprehensively analyzed the RNA kinome sequence, but no universal gene alterations were detected in naquotinib-resistant cells. Neuroblastoma RAS viral oncogene homolog (NRAS) amplification was detected in naquotinib-resistant cells derived from gefitinib-resistant cells. The combination therapy of MEK inhibitors and naquotinib exhibited a highly beneficial effect in resistant cells with NRAS amplification, but the combination of MEK inhibitors and osimertinib had limited effects on naquotinib-resistant cells. Moreover, the combination of MEK inhibitors and naquotinib inhibited the growth of osimertinib-resistant cells, while the combination of MEK inhibitors and osimertinib had little effect on osimertinib-resistant cells. Clinical assessment of this novel combination (MEK inhibitors and naquotinib) is worth considering in osimertinib-resistant lung tumors.

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  • Transduced caudal-type homeobox (CDX) 2/CDX1 can induce growth inhibition on CDX-deficient gastric cancer by rapid intestinal differentiation. Reviewed International journal

    Nakayama C, Yamamichi N, Tomida S, Takahashi Y, Kageyama-Yahara N, Sakurai K, Takeuchi C, Inada KI, Shiogama K, Nagae G, Ono S, Tsuji Y, Niimi K, Fujishiro M, Aburatani H, Tsutsumi Y, Koike K

    Cancer science   109 ( 12 )   3853 - 3864   2018.12

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    Intestinal metaplasia induced by ectopic expression of caudal-type homeobox (CDX)2 and/or CDX1 (CDX) is frequently observed around gastric cancer (GC). Abnormal expression of CDX is also observed in GC and suggests that inappropriate gastrointestinal differentiation plays essential roles in gastric tumorigenesis, but their roles on tumorigenesis remain unelucidated. Publicly available databases show that GC patients with higher CDX expression have significantly better clinical outcomes. We introduced CDX2 and CDX1 genes separately into GC-originated MKN7 and TMK1 cells deficient in CDX. Marked suppression of cell growth and dramatic morphological change into spindle-shaped flat form were observed along with induction of intestinal marker genes. G0-G1 growth arrest was accompanied by changed expression of cell cycle-related genes but not with apoptosis or senescence. Microarray analyses additionally showed decreased expression of gastric marker genes and increased expression of stemness-associated genes. Hierarchical clustering of 111 GC tissues and 21 non-cancerous gastric tissues by selected 18 signature genes based on our transcriptome analyses clearly categorized the 132 tissues into non-cancer, "CDX signature"-positive GC, and "CDX signature"-negative GC. Gene set enrichment analysis indicated that "CDX signature"-positive GC has lower malignant features. Immunohistochemistry of 89 GC specimens showed that 50.6% were CDX2-deficient, 66.3% were CDX1-deficient, and 44.9% were concomitant CDX2/CDX1-deficient, suggesting that potentially targetable GC cases by induced intestinal differentiation are quite common. In conclusion, exogenous expression of CDX2/CDX1 can lead to efficient growth inhibition of CDX-deficient GC cells. It is based on rapidly induced intestinal differentiation, which may be a future therapeutic strategy.

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  • Comparative mutational evaluation of multiple lung cancers by multiplex oncogene mutation analysis. Reviewed International journal

    Yuta Takahashi, Kazuhiko Shien, Shuta Tomida, Shinsuke Oda, Takehiro Matsubara, Hiroki Sato, Ken Suzawa, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Takahiro Yoshioka, Hidejiro Torigoe, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka

    Cancer science   109 ( 11 )   3634 - 3642   2018.11

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    In patients presenting with synchronous or metachronous multiple lung cancer (MLC), it is important to distinguish between multiple primary lung cancer (MP) and intrapulmonary metastasis (IM). The present study was aimed at investigating the mutational profiles of synchronous/metachronous MLC and to compare the classification of paired tumors by multiplex gene mutation analysis with the histopathological evaluation. We carried out targeted sequencing of 20 lung cancer-related oncogenes using next-generation sequencing (NGS) in 82 tumors from 37 MLC patients who underwent surgical resection at our department. The patients were diagnosed as MP or IM cases based on the Martini and Melamed criteria, histopathological and gene mutational evaluations. Matching mutations between paired tumors was observed in 20 (54%) patients, who were diagnosed as IM cases by mutational evaluation. Patients who could not be clearly diagnosed by histopathological evaluation were classified as equivocal cases. Among the histopathological IM cases (n = 7), six (86%) were confirmed as IM cases also by mutational evaluation, and most of the paired tumors of these cases (n = 5) harbored multiple matching mutations. Among the histopathological MP cases (n = 17), mutational evaluation yielded a discordant diagnosis in eight (47%) cases. Of these, the paired tumors of four cases harbored multiple matching mutations, suggesting that the mutational diagnosis might be more suitable in these patients. Our findings suggest that multiplex mutational analysis could be a useful complementary tool for distinguishing between MP and IM in addition to histopathological evaluation.

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  • Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer. Reviewed International journal

    Hiroki Sato, Hiromasa Yamamoto, Masakiyo Sakaguchi, Kazuhiko Shien, Shuta Tomida, Tadahiko Shien, Hirokuni Ikeda, Minami Hatono, Hidejiro Torigoe, Kei Namba, Takahiro Yoshioka, Eisuke Kurihara, Yusuke Ogoshi, Yuta Takahashi, Junichi Soh, Shinichi Toyooka

    Cancer science   109 ( 10 )   3183 - 3196   2018.10

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    Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non-small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide-3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR-TKI-resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single-agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal-epithelial transition factor amplification, induction of epithelial-to-mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long-term treatment with the combination therapy induced the conversion from EMT to mesenchymal-to-epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR-TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR-TKIs.

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  • Integrated fluorescent cytology with nano-biologics in peritoneally disseminated gastric cancer. Reviewed International journal

    Watanabe M, Kagawa S, Kuwada K, Hashimoto Y, Shigeyasu K, Ishida M, Sakamoto S, Ito A, Kikuchi S, Kuroda S, Kishimoto H, Tomida S, Yoshida R, Tazawa H, Urata Y, Fujiwara T

    Cancer science   109 ( 10 )   3263 - 3271   2018.10

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    Gastric cancer patients positive for peritoneal cytology are at increased risk of tumor recurrence, but although a certain proportion of cytology-positive patients relapse rapidly with aggressive progression, others survive longer with conventional chemotherapies. This heterogeneity makes it difficult to stratify patients for more intensive therapy and poses a substantial challenge for the implementation of precision medicine. We developed a new approach to identify biologically malignant subpopulations in cytology-positive gastric cancer patients, using a green fluorescent protein (GFP)-expressing attenuated adenovirus in which the telomerase promoter regulates viral replication (TelomeScan, OBP-401). The fluorescence emitted from TelomeScan-positive cells was successfully quantified using a multi-mode microplate reader. We then analyzed clinical peritoneal washes obtained from 68 gastric cancer patients and found that patients positive for TelomeScan had a significantly worse prognosis. In 21 cytology-positive patients, the median survival time of those who were TelomeScan positive (235 days) was significantly shorter than that for those who were TelomeScan negative (671 days; P = 0.0062). This fluorescent virus-guided cytology detects biologically malignant cancer cells from the peritoneal washes of gastric cancer patients and may thus be useful for both therapy stratification and precision medicine approaches based on genetic profiling of disseminated cells.

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  • Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions. Reviewed International journal

    Kato Y, Ninomiya K, Ohashi K, Tomida S, Makimoto G, Watanabe H, Kudo K, Matsumoto S, Umemura S, Goto K, Ichihara E, Ninomiya T, Kubo T, Sato A, Hotta K, Tabata M, Toyooka S, Maeda Y, Kiura K

    Cancer science   109 ( 10 )   3149 - 3158   2018.10

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    The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non-small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2-ROS1 and ABC-20 harboring CD74-ROS1, were used as cell line-based resistance models. Crizotinib-resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor-receptor tyrosine kinase array and RNA sequence analysis by next-generation sequencing. HCC78R cells showed upregulation of HB-EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB-EGF or EGF rendered HCC78 cells or ABC-20 cells resistant to crizotinib. RNA sequence analysis by next-generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR-TKI or anti-EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR-TKI were more effective against HCC78R cells than monotherapy with an EGFR-TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB-EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR-TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.

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  • デジタルPCR法による呼気濃縮液を用いたEGFR遺伝子診断法の検討

    西井 和也, 大橋 圭明, 田村 朋季, 妹尾 賢, 狩野 裕久, 渡邉 洋美, 小田 尚廣, 槇本 剛, 肥後 寿夫, 二宮 貴一朗, 加藤 有加, 南 大輔, 二宮 崇, 久保 寿夫, 堀田 勝幸, 田端 雅弘, 冨田 秀太, 豊岡 伸一, 前田 嘉信, 木浦 勝行

    肺癌   58 ( 6 )   597 - 597   2018.10

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  • 肺癌におけるPrecision Medicineの現状と今後の展開 肺癌のゲノム異常と治療の課題

    豊岡 伸一, 枝園 和彦, 山本 寛斉, 宗 淳一, 冨田 秀太

    日本癌治療学会学術集会抄録集   56回   PD3 - 2   2018.10

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  • HER増幅胃癌におけるアファチニブ耐性機序(Acquired resistant mechanism to afatinib in HER2 amplified gastric cancer cells)

    吉岡 貴裕, 枝園 和彦, 難波 圭, 冨田 秀太, 山本 寛斉, 宗 淳一, 藤原 俊義, 豊岡 伸一

    日本癌学会総会記事   77回   1449 - 1449   2018.9

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  • EGFR変異陽性肺癌におけるLRIG1の抗腫瘍効果(Tumor-suppressive effect of LRIG1 in non-small cell lung cancer harboring mutant EGFR)

    鳥越 英次郎, 山本 寛斉, 阪口 政清, 難波 圭, 佐藤 博紀, 枝園 和彦, 諏澤 憲, 宗 淳一, 冨田 秀太, 佃 和憲, 三好 新一郎, 豊岡 伸一

    日本癌学会総会記事   77回   940 - 940   2018.9

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  • 腫瘍浸潤リンパ球(TIL)を含んだ腫瘍解離細胞(DTC)の保存

    渡邊 元嗣, 高橋 優太, 冨田 秀太, 宗 淳一, 松原 岳大, 難波 圭, 佐藤 博紀, 森田 瑞樹, 枝園 和彦, 山本 寛斉, 鵜殿 平一郎, 豊岡 伸一

    日本がん免疫学会総会プログラム・抄録集   22回   161 - 161   2018.7

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  • Identification of marker genes and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas Reviewed

    Yoshiki Sakaguchi, Nobutake Yamamichi, Shuta Tomida, Chihiro Takeuchi, Natsuko Kageyama-Yahara, Yu Takahashi, Kazuya Shiogama, Ken-ichi Inada, Masao Ichinose, Mitsuhiro Fujishiro, Kazuhiko Koike

    Journal of Gastroenterology   54 ( 2 )   1 - 10   2018.6

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    Background: The mechanism behind the pathogenesis and carcinogenesis of these neoplasms is not fully understood. The objective of this study was to identify genetic markers and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas through gene expression analysis. Methods: Gene expression profiling was performed in 4 pairs of duodenal adenoma/adenocarcinomas and corresponding matched normal tissue. Genes with consistent expression differences were identified and confirmed in 7 independent pairs. Gene set enrichment analysis (GSEA) was performed to characterize gene expression profiles of duodenal adenoma/adenocarcinomas, together with immunohistochemical staining of candidate oncogenic genes. Results: 626 probes consistently demonstrated over a twofold expression difference between tumor–normal pairs. Reverse transcriptase polymerase chain reaction of genes with the most prominent difference in expression between tumors and normal mucosa (KLK7, KLK6, CEMIP, MMP7, KRT17, LGR5, G6PC, S100G, APOA1) validated the results of gene expression analysis. GSEA demonstrated a strong association between duodenal adenoma/adenocarcinomas with colorectal adenomas (p &lt
    10−5) and gene expression patterns seen after APC gene knockout (p &lt
    10−5), suggesting that the Wnt/β-catenin pathway plays a crucial role in the carcinogenesis of these neoplasms. Immunohistochemical staining of an independent group of duodenal adenomas confirmed over-accumulation of β-catenin in 80.0% (16/20). Conclusions: Precancerous duodenal adenomas and early stage adenocarcinomas demonstrate gene expression characteristics with a strong resemblance to colorectal adenomas. The results of this study strongly suggest that upregulation of the Wnt/β-catenin pathway is the major factor involved in the initial stages of the carcinogenesis of duodenal adenocarcinomas.

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  • Tumor-suppressive effect of LRIG1, a negative regulator of ErbB, in non-small cell lung cancer harboring mutant EGFR. Reviewed International journal

    Hidejiro Torigoe, Hiromasa Yamamoto, Masakiyo Sakaguchi, Chen Youyi, Kei Namba, Hiroki Sato, Kazuhiko Shien, Junichi Soh, Ken Suzawa, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    Carcinogenesis   39 ( 5 )   719 - 727   2018.5

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    Epidermal growth factor receptor (EGFR) is a member of the ErbB (HER) family that is known to play important roles in the pathogenesis of various human cancers. Mutations of the EGFR gene are commonly found as oncogenic driver mutations and have been targeted for treatment of non-small cell lung cancer (NSCLC). Leucine-rich repeat and immunoglobulin-like domain protein-1 (LRIG1) is a cell-surface protein that is known as a negative regulator of the ErbB (HER) family. In this study, we first confirmed that the expression levels of LRIG1 were much lower in NSCLC than in non-malignant cells or tissues. Next, we focused on the effect of LRIG1 in NSCLC. For this purpose, we established clones stably overexpressing LRIG1, using EGFR-mutant (HCC827, HCC4011 and NCI-H1975) and wild-type (A549) cells. Transfection of LRIG1 was associated with a decrease in the expression and phosphorylation levels of EGFR in the HCC827, HCC4011 and NCI-H1975 cells. It was also associated with strong suppression of the cell proliferative, invasive, migratory and tumorigenic potential of the HCC827 cells. On the other hand, no such effects were observed in the A549 cells. In addition, LRIG1 also downregulated the expression and phosphorylation levels of other tyrosine kinase receptors, such as HER2, HER3, MET and IGF-1R, and prevented the epithelial-to-mesenchymal transition induced by TGF-β in the HCC827 cells. These findings suggest that LRIG1 exerts important tumor-suppressive effects in EGFR-mutant NSCLC and has the potential to become a novel therapeutic target for EGFR-mutant NSCLC.

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  • Therapeutic strategies for afatinib-resistant lung cancer harboring HER2 alterations Reviewed

    Hidejiro Torigoe, Kazuhiko Shien, Tatsuaki Takeda, Takahiro Yoshioka, Kei Namba, Hiroki Sato, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Masakiyo Sakaguchi, Shuta Tomida, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    Cancer Science   109 ( 5 )   1493 - 1502   2018.5

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    Human epidermal growth factor receptor 2 (HER2) plays an important role in the pathogenesis of various cancers. HER2 alterations have been suggested to be a therapeutic target in non-small-cell lung cancer (NSCLC), just as in breast and gastric cancers. We previously reported that the pan-HER inhibitor afatinib could be a useful therapeutic agent as HER2-targeted therapy for patients with NSCLC harboring HER2 alterations. However, acquired resistance to afatinib was observed in the clinical setting, similar to the case for other HER inhibitors. Thus, elucidation of the mechanisms underlying the development of acquired drug resistance and exploring means to overcome acquired drug resistance are important issues in the treatment of NSCLC. In this study, we experimentally established afatinib-resistant cell lines from NSCLC cell lines harboring HER2 alterations, and investigated the mechanisms underlying the acquisition of drug resistance. The established cell lines showed several unique afatinib-resistance mechanisms, including MET amplification, loss of HER2 amplification and gene expression, epithelial-to-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. The afatinib-resistant cell lines showing MET amplification were sensitive to the combination of afatinib plus crizotinib (a MET inhibitor), both in vitro and in vivo. The resistant cell lines which showed EMT or had acquired CSC-like features remained sensitive to docetaxel, like the parental cells. These findings may provide clues to countering the resistance to afatinib in NSCLC patients with HER2 alterations.

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  • Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers. Reviewed International journal

    Hiroshi Kotani, Yuta Adachi, Hidenori Kitai, Shuta Tomida, Hideaki Bando, Anthony C Faber, Takayuki Yoshino, Dominic C Voon, Seiji Yano, Hiromichi Ebi

    Oncogene   37 ( 13 )   1775 - 1787   2018.3

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    BRAF is one of the most frequently mutated genes across a number of different cancers, with the best-characterized mutation being V600E. Despite the successes of treating BRAF mutant V600E lung cancer with BRAF pathway inhibitors, treatment strategies targeting tumors with non-V600E mutations are yet to be established. We studied cellular signaling differences between lung cancers with different BRAF mutations and determined their sensitivities to BRAF pathway inhibitors. Here, we observed that MEK inhibition induced feedback activation of the receptor tyrosine kinase (RTK) EGFR, and in some cases the RTK FGFR, resulting in transient suppression of ERK phosphorylation in BRAF non-V600E, but not BRAF V600E, mutant cells. Furthermore, we found that both EGFR and FGFR activated the MEK/ERK pathway, despite the presence of BRAF non-V600E mutations with elevated kinase activity. Moreover, in BRAF non-V600E mutants with impaired kinase activities, EGFR had even greater control over the MEK/ERK pathway, essentially contributing completely to the tonic mitogen-activated protein kinase (MAPK) signal. Accordingly, the combination of MEK inhibitor with EGFR inhibitor was effective at shrinking tumors in mouse model of BRAF non-V600E mutant lung cancer. Furthermore, the results were recapitulated with a clinically relevant dual inhibitor of EGFR and RAF, BGB-283. Overall, although BRAF V600E mutant cells are sensitive to BRAF inhibition, non-V600E mutant cancer cells are reliant on RTKs for their MAPK activation and inhibiting both MEK and RTKs are necessary in these cancers. Our findings provide evidence of critical survival signals in BRAF non-V600E mutant cancers, which could pave the way for effective treatment of these cancers.

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  • Therapeutic Potential of Afatinib for Cancers with ERBB2 (HER2) Transmembrane Domain Mutations G660D and V659E Reviewed

    Hiromasa Yamamoto, Shinichi Toyooka, Takashi Ninomiya, Shigemi Matsumoto, Masashi Kanai, Shuta Tomida, Katsuyuki Kiura, Manabu Muto, Ken Suzawa, Patrice Desmeules, Mark G. Kris, Bob T. Li, Marc Ladanyi

    Oncologist   23 ( 2 )   150 - 154   2018.2

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    We previously reported on a family with hereditary lung cancer, in which a germline mutation in the transmembrane domain (G660D) of avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2
    human epidermal growth factor receptor 2 [HER2]) seemed to be responsible for the cancer predisposition. Although few data are available on treatment, anti-ERBB2 therapeutic agents may be effective for ERBB2-mutant cancers. The familial lung cancer patient in one of the authors’ institutes developed bone metastasis with enlarging lung tumors and was treated with the ERBB2 inhibitor afatinib. We also encountered a patient with ampullary adenocarcinoma with ERBB2 G660D and S310F comutations in another institute of the authors’, revealed by comprehensive genomic profiling. This patient was then treated with afatinib and also achieved transitory response. We also searched for ERBB2 transmembrane mutations in various types of cancers in PubMed, The Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) database. Besides our two cases, two patients with V659E mutations were found via PubMed. Three potential patients were found in TCGA. In addition, MSK-IMPACT allowed identification of three additional urothelial carcinomas with G660D mutations and two lung adenocarcinomas with V659E mutations. Our experience suggests that establishing a database of integrated information regarding the clinical genome and therapeutic outcome of patients with recurrent but less common mutations is essential to implement precision oncology. Key Points: Rare but targetable mutations such as avian erythroblastic leukemia viral oncogene homolog 2 (erb-b2 receptor tyrosine kinase 2) (ERBB2
    human epidermal growth factor receptor 2 [HER2]) transmembrane domain (TMD) mutations can be detected by comprehensive genomic profiling. Afatinib may be effective for patients with cancer with ERBB2 (HER2) TMD mutations. In order to implement precision oncology, it is important to establish a database of integrated information regarding the clinical genomes and therapeutic outcomes of patients with recurrent but less common mutations.

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  • CCL28-Deficient Mice Have Reduced IgA Antibody-Secreting Cells and an Altered Microbiota in the Colon. Reviewed International journal

    Kazuhiko Matsuo, Daisuke Nagakubo, Shinya Yamamoto, Akiko Shigeta, Shuta Tomida, Mitsugu Fujita, Takako Hirata, Ikuo Tsunoda, Takashi Nakayama, Osamu Yoshie

    Journal of immunology (Baltimore, Md. : 1950)   200 ( 2 )   800 - 809   2018.1

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    CCL28 induces the migration of IgA Ab-secreting cells (ASCs) via CCR10 and also displays a potent antimicrobial activity in vitro. To explore the role of CCL28 in vivo, we generated CCL28-deficient mice. The mice exhibited a significant reduction and abnormal distribution of IgA ASCs in the lamina propria of the colon. The concentrations of total and Ag-specific IgA in the fecal extracts of CCL28-deficient mice were also drastically reduced. The average amount of IgA secreted by a single IgA ASC derived from the colon was also substantially reduced in CCL28-deficient mice. Furthermore, CCL28 was found to significantly increase the average amount of IgA secreted by a single IgA ASC derived from the colon in vitro. In contrast, the generation of IgA ASCs in Peyer's and cecal patches was not significantly impaired in CCL28-deficient mice. We also found a relative increase in the Class Bacilli in the fecal extracts of CCL28-deficient mice and demonstrated a potent antimicrobial activity of CCL28 against Bacillus cereus and Enterococcus faecalis, both of which belong to Class Bacilli. Thus, CCL28 may also suppress the outgrowth of some bacterial species by its direct antimicrobial activity. Finally, CCL28-deficient mice exhibited a highly aggravated dextran sodium sulfate-induced colitis that was ameliorated by pretreatment with antibiotics. Collectively, CCL28 plays a pivotal role in the homing, distribution, and function of IgA ASCs in the colon and may also affect the intestinal microbiota through its direct antimicrobial activity.

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  • Therapeutic potential of targeting S100A11 in malignant pleural mesothelioma Reviewed

    Hiroki Sato, Masakiyo Sakaguchi, Hiromasa Yamamoto, Shuta Tomida, Keisuke Aoe, Kazuhiko Shien, Takahiro Yoshioka, Kei Namba, Hidejiro Torigoe, Junichi Soh, Kazunori Tsukuda, Hiroyuki Tao, Kazunori Okabe, Shinichiro Miyoshi, Harvey I. Pass, Shinichi Toyooka

    Oncogenesis   7 ( 1 )   11   2018.1

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    Malignant pleural mesothelioma (MPM) is an aggressive tumor with an unfavorable prognosis. The standard therapeutic approaches are limited to surgery, chemotherapy, and radiotherapy. Because the consequent clinical outcome is often unsatisfactory, a different approach in MPM treatment is required. S100A11, a Ca2+-binding small protein with two EF-hands, is frequently upregulated in various human cancers. Interestingly, it has been found that intracellular and extracellular S100A11 have different functions in cell viability. In this study, we focused on the impact of extracellular S100A11 in MPM and explored the therapeutic potential of an S100A11-targeting strategy. We examined the secretion level of S100A11 in various kinds of cell lines by enzyme-linked immunosorbent assay. Among them, six out of seven MPM cell lines actively secreted S100A11, whereas normal mesothelial cell lines did not secrete it. To investigate the role of secreted S100A11 in MPM, we inhibited its function by neutralizing S100A11 with an anti-S100A11 antibody. Interestingly, the antibody significantly inhibited the proliferation of S100A11-secreting MPM cells in vitro and in vivo. Microarray analysis revealed that several pathways including genes involved in cell proliferation were negatively enriched in the antibody-treated cell lines. In addition, we examined the secretion level of S100A11 in various types of pleural effusions. We found that the secretion of S100A11 was significantly higher in MPM pleural effusions, compared to others, suggesting the possibility for the use of S100A11 as a biomarker. In conclusion, our results indicate that extracellular S100A11 plays important roles in MPM and may be a therapeutic target in S100A11-secreting MPM.

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  • Development of novel biologics for cancer metastasis via prevention of extracellular S100A8/A9 function Reviewed

    Kinoshita Rie, Yamauchi Akira, Shien Kazuhiko, Tomida Shuta, Toyooka Shinichi, Kondo Eisaku, Sakaguchi Masakiyo

    CANCER SCIENCE   109   1017   2018.1

  • Elacridar, a third-generation ABCB1 inhibitor, overcomes resistance to docetaxel in non-small cell lung cancer Reviewed

    Haiyang Chen, Kazuhiko Shien, Ken Suzawa, Kazunori Tsukuda, Shuta Tomida, Hiroki Sato, Hidejiro Torigoe, Mototsugu Watanabe, Kei Namba, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Shinichiro Miyoshi, Shinichi Toyooka

    ONCOLOGY LETTERS   14 ( 4 )   4349 - 4354   2017.10

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    Docetaxel is a third-generation chemotherapeutic drug that is widely used in the treatment of patients with non-small cell lung cancer (NSCLC). However, the majority of patients with NSCLC eventually acquire resistance to the treatment. In the present study, the mechanism of acquired resistance to docetaxel treatment in lung cancer cells was investigated. The three NSCLC cell lines, H1299 with wild-type epidermal growth factor receptor (EGFR), EGFR-mutant HCC4006 and HCC827, and experimentally established docetaxel-resistant (DR) cells, H1299-DR, HCC827-DR, and HCC4006-DR were used with stepwise increases in concentrations of docetaxel. It was demonstrated that the established cell lines showed resistance to docetaxel and EGFR-tyrosine kinase inhibitors (TKIs). Molecular analysis revealed that all of the resistant cell lines highly expressed ATP binding cassette subfamily B member 1 (ABCB1), which is also known as P-glycoprotein or MDR1. Furthermore, HCC827-DR and HCC4006-DR cells exhibited a cancer stem cell-like marker and epithelial-to-mesenchymal transition features, respectively. Elacridar (GF120918), a third-generation inhibitor of ABCB1, was able to overcome resistance to docetaxel. Additionally, knockdown of ABCB1 using small interfering RNA (si)-ABCB1 recovered sensitivity to docetaxel. However, elacridar and si-ABCB1 could not recover sensitivity to EGFR-TKIs in established resistant cells. The results of the present study revealed that docetaxelresis-tant NSCLC cells also acquired cross-resistance to EGFR-TKI therapy through mechanisms other than ABCB1, that ABCB1 serves an important role in acquired resistance to docetaxel in lung cancer, and that combination therapy with elacridar can overcome ABCB1-mediated docetaxel resistance.

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  • Effects of Cold Ischemia on RNA Stability and Quality of Lung Tissues Based on Standard PREanalytical Code Categorization Reviewed

    Takehiro Matsubara, Shuta Tomida, Junichi Soh, Takahiro Uwabo, Yoshiko Mori, Mizuki Morita, Yasutomo Nasu, Susumu Kanazawa, Shinichi Toyooka

    BIOPRESERVATION AND BIOBANKING   15 ( 5 )   484 - 486   2017.10

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  • Induction chemoradiotherapy using docetaxel and cisplatin with definitive-dose radiation followed by surgery for locally advanced non-small cell lung cancer Reviewed

    Hidejiro Torigoe, Junichi Soh, Shuta Tomida, Kei Namba, Hiroki Sato, Kuniaki Katsui, Katsuyuki Hotta, Kazuhiko Shien, Hiromasa Yamamoto, Masaomi Yamane, Susumu Kanazawa, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

    JOURNAL OF THORACIC DISEASE   9 ( 9 )   3076 - 3086   2017.9

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    Background: Induction chemoradiotherapy (CRT) followed by surgery is a therapeutic option for locally advanced non-small cell lung cancer (LA-NSCLC). Typically, around 40-50 Gy of radiation is applied as the induction-dose; however, a definitive-dose (DD) of radiation (60 Gy or higher) is occasionally applied to increase local control. We investigated the impact of induction CRT with DD radiation in LA-NSCLC patients treated with a single regimen of docetaxel and cisplatin.
    Methods: We reviewed 110 patients with LA-NSCLC who underwent induction CRT followed by surgery using a single regimen (docetaxel and cisplatin) between January 1999 and December 2014 at our hospital. The clinical outcomes of a DD group (60 Gy or higher, n= 11) and a non-DD group (less than 60 Gy, n= 99) were investigated using a propensity score (PS)-matched analysis.
    Results: An advanced clinical stage was significantly more common in the DD group than in the nonDD group (P= 0.033). Before and after the PS-matching based on seven factors including clinical stage, there was no significant difference in the rates of postoperative (PO) complication, mortality, 5-year overall survival (OS), or 5-year recurrence-free survival (RFS) between the two groups. After the PS-matching, the pathological complete response (CR) rate was significantly higher in the DD group than in the non-DD group [50% (n= 5/10) vs. 0% (n= 0/10), P= 0.033].
    Conclusions: Induction CRT followed by surgery using docetaxel and cisplatin with DD radiation can be performed safely and is associated with a higher pathological CR rate than that attained using non-DD radiation in LA-NSCLC patients.

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  • 分子バーコード技術を用いた低頻度多重変異の同定

    難波 圭, 冨田 秀太, 枝園 和彦, 山本 寛斉, 宗 淳一, 佃 和憲, 豊岡 伸一

    日本癌学会総会記事   76回   P - 3052   2017.9

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  • HER2遺伝子異常肺癌に対するマルチキナーゼ阻害剤Afatinb耐性獲得機序の解明

    鳥越 英次郎, 枝園 和彦, 吉岡 貴裕, 難波 圭, 佐藤 博紀, 山本 寛斉, 宗 淳一, 浅野 博昭, 冨田 秀太, 佃 和憲, 豊岡 伸一

    肺癌   57 ( 5 )   441 - 441   2017.9

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  • 肺がん新治療の展望 HER2異常肺癌に対する治療戦略

    豊岡 伸一, 諏澤 憲, 二宮 崇, 山本 寛斉, 枝園 和彦, 宗 淳一, 冨田 秀太, 木浦 勝行

    日本癌学会総会記事   76回   SST6 - 3   2017.9

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  • 抗HER2療法耐性におけるYes1の重要性

    武田 達明, 山本 寛斉, 諏澤 憲, 冨田 秀太, 難波 圭, 渡邉 元嗣, 枝園 和彦, 宗 淳一, 佃 和憲, 豊岡 伸一

    日本癌学会総会記事   76回   P - 3366   2017.9

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  • PIK3R1Met326Ile germline mutation correlates with cysteine-rich protein 61 expression and poor prognosis in glioblastoma Reviewed

    Yoshihiro Otani, Joji Ishida, Kazuhiko Kurozumi, Tetsuo Oka, Toshihiko Shimizu, Yusuke Tomita, Yasuhiko Hattori, Atsuhito Uneda, Yuji Matsumoto, Hiroyuki Michiue, Shuta Tomida, Takehiro Matsubara, Tomotsugu Ichikawa, Isao Date

    SCIENTIFIC REPORTS   7 ( 1 )   7391   2017.8

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    Despite therapeutic advances, glioblastoma represents a lethal brain tumor. Recently, research to identify prognostic markers for glioblastoma has intensified. Our previous study demonstrated that median progression-free survival (PFS) and overall survival (OS) of patients with high cysteine-rich protein 61 (CCN1) expression was significantly shorter than that of patients with low CCN1 expression. To understand the molecular mechanisms that regulate CCN1 expression, we examined 147 tumour samples from 80 patients with glioblastoma and 67 patients with lower grade glioma. Next-generation and Sanger sequencing showed that PIK3R1Met326Ile was more frequent in the CCN1 high expression group (10/37 cases, 27.0%) than the CCN1 low expression group (3/38 cases, 7.9%) in glioblastoma. This mutation was also detected in corresponding blood samples. In multivariate analysis, high CCN1 expression and PIK3R1Met326Ile in glioblastoma patients were prognostic factors for OS [HR = 2.488 (1.298-4.769), p = 0.006] and [HR = 2.089 (1.020-4.277), p = 0.0439], respectively. Thus, the PIK3R1Met326Ile germline appears to be correlated with CCN1 expression and poor prognosis in glioblastoma.

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  • Optimal method for quantitative detection of plasma EGFR T790M mutation using droplet digital PCR system Reviewed

    Ken Suzawa, Hiromasa Yamamoto, Kadoaki Ohashi, Shinsuke Hashida, Shuta Tomida, Toshio Kubo, Yuho Maki, Junichi Soh, Kazunori Tsukuda, Katsuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

    ONCOLOGY REPORTS   37 ( 5 )   3100 - 3106   2017.5

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    Though patients with EGFR mutations are initially responsive to EGFR-tyrosine kinase inhibitors (TKIs), most tumors ultimately acquire resistance to EGFR-TKIs. The most frequently reported mechanism is EGFR T790M mutation. In this study, using a droplet digital PCR (ddPCR) system, we assessed optimal conditions for a mutation detection assay for EGFR T790M obtained from circulating cell-free DNA (cfDNA) in plasma. The advantages of locked nucleic acids (LNA) probe, short amplicon size, and blocking oligo using peptide nucleic acids (PNA) were assessed using control DNAs from cell lines to improve the sensitivity of mutation detection. T790M alleles were then analyzed using ddPCR in 59 plasma samples from 24 NSCLC patients with EGFR mutations, and compared to the T790M status which were determined thorough re-biopsies. The assessment of the optimal assay method revealed that the assay using the short amplicon can efficiently detect more fragmented-DNA. The LNA probe and PNA clamp contributed better separation between positive and negative droplets. This PNA-LNA-ddPCR clamp method can detect mutant alleles in the sample with a mutant allele content of 0.01%. In clinical plasma samples, T790M alleles were detected via ddPCR with a sensitivity of 42.8% and specificity of 97.3%. We established a highly-sensitive detection assay for the T790M allele using the PNA-LNA-ddPCR clamp method. ddPCR is a promising method for detecting non-invasive T790M mutation.

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  • Lung Cancer Panelを用いた多発小型肺癌のマルチプレックス遺伝子変異解析

    枝園 和彦, 冨田 秀太, 佐藤 博紀, 高橋 優太, 諏澤 憲, 山本 寛斉, 宗 淳一, 三好 新一郎, 豊岡 伸一

    日本呼吸器外科学会雑誌   31 ( 3 )   RO16 - 4   2017.4

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  • The H3K27 demethylase, Utx, regulates adipogenesis in a differentiation stagedependent manner Reviewed

    Kazushige Ota, Kit I. Tong, Kouichiro Goto, Shuta Tomida, Akiyoshi Komuro, Zhong Wang, Kazuto Nishio, Hitoshi Okada

    PLOS ONE   12 ( 3 )   e0173713   2017.3

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    Understanding the molecular mechanisms that drive adipogenesis is important in developing new treatments for obesity and diabetes. Epigenetic regulations determine the capacity of adipogenesis. In this study, we examined the role of a histone H3 lysine 27 demethylase, the ubiquitously transcribed tetratricopeptide repeat protein on the X chromosome (Utx), in the differentiation of mouse embryonic stem cells (mESCs) to adipocytes. Using gene trapping, we examined Utx-deficient male mESCs to determine whether loss of Utx would enhance or inhibit the differentiation of mESCs to adipocytes. Utx-deficient mESCs showed diminished potential to differentiate to adipocytes compared to that of controls. In contrast, Utx-deficient preadipocytes showed enhanced differentiation to adipocytes. Microarray analyses indicated that the beta-catenin/c-Myc signaling pathway was differentially regulated in Utx-deficient cells during adipocyte differentiation. Therefore, our data suggest that Utx governs adipogenesis by regulating c-Myc in a differentiation stage-specific manner and that targeting the Utx signaling pathway could be beneficial for the treatment of obesity, diabetes, and congenital utx-deficiency disorders.

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  • Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer (vol 12, e0171356, 2017) Reviewed

    T. Takeda, H. Yamamoto, H. Kanzaki, K. Suzawa, T. Yoshioka, S. Tomida

    PLOS ONE   12 ( 3 )   e0171356   2017.3

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  • Draft Genome Sequence of Bifidobacterium lemurum DSM 28807T Isolated from the Gastrointestinal Tracts of Ring-Tailed Lemurs (Lemur catta) Reviewed

    Hidehiro Toh, Takehiro Matsubara, Shuta Tomida, Iyo Mimura, Kensuke Arakawa, Takefumi Kikusui, Hidetoshi Morita

    Genome Announcements   5 ( 8 )   2017.2

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    <named-content content-type="genus-species">Bifidobacterium lemurum</named-content> DSM 28807T was isolated from the gastrointestinal tracts of ring-tailed lemurs (<italic>Lemur catta</italic>). Here, we report the first draft genome sequence of this organism.

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  • Yes1 signaling mediates the resistance to Trastuzumab/Lap atinib in breast cancer Reviewed

    Tatsuaki Takeda, Hiromasa Yamamoto, Hirotaka Kanzaki, Ken Suzawa, Takahiro Yoshioka, Shuta Tomida, Xiaojiang Cui, Ramachandran Murali, Kei Namba, Hiroki Sato, Hidejiro Torigoe, Mototsugu Watanabe, Kazuhiko Shien, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Yoshihisa Kitamura, Shinichiro Miyoshi, Toshiaki Sendo, Shinichi Toyooka

    PLOS ONE   12 ( 2 )   2017.2

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    Background
    Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in approximately 15-23% of breast cancers and these cancers are classified as HER2-positive breast cancer. Trastuzumab is the first-line targeted therapeutic drug for HER2-positive breast cancer and has improved patient overall survival. However, acquired resistance to trastuzumab is still a critical issue in breast cancer treatment. We previously established a trastuzumabresistant breast cancer cell line (named as BT-474-R) from a trastuzumab-sensitive HER2-amplified cell line BT-474. Lapatinib is also a molecular-targeted drug for HER2-positive breast cancer, which acquired the resistance to trastuzumab. Acquired resistance to lapatinib is also an issue to be conquered.
    Methods
    We established trastuzumab/lapatinib-dual resistant cell line (named as BT-474-RL2) by additionally treating BT-474-R with lapatinib. We analyzed the mechanisms of resistance to trastuzumab and lapatinib. Besides, we analyzed the effect of the detected resistance mechanism in HER2-positive breast cancer patients.
    Results
    Proto-oncogene tyrosine-protein kinase Yes1, which is one of the Src family members, was amplified, overexpressed and activated in BT-474-R and BT-474-RL2. Silencing of Yes1 by siRNA induced both BT-474-R and BT-474-RL2 to restore the sensitivity to trastuzumab and lapatinib. Pharmaceutical inhibition of Yes1 by the Src inhibitor dasatinib was also effective to restore the sensitivity to trastuzumab and lapatinib in the two resistant cell lines. Combination treatment with dasatinib and trastuzumab induced down-regulation of signaling molecules such as HER2 and Akt. Moreover, the combination treatments induced G1-phase cell-cycle arrest and apoptosis. Consistent with cell line data, high expression of Yes1 mRNA was correlated with worse prognosis in patients with HER2-positive breast cancer.
    Conclusion
    Yes1 plays an important role in acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancer. Our data suggest that pharmacological inhibition of Yes1 may be an effective strategy to overcome resistance to trastuzumab and lapatinib.

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  • Comparative genome analyses of Mycobacterium avium reveal genomic features of its subspecies and strains that cause progression of pulmonary disease Reviewed

    Kei-ichi Uchiya, Shuta Tomida, Taku Nakagawa, Shoki Asahi, Toshiaki Nikai, Kenji Ogawa

    SCIENTIFIC REPORTS   7   39750   2017.1

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    Pulmonary disease caused by nontuberculous mycobacteria (NTM) is increasing worldwide. Mycobacterium avium is the most clinically significant NTM species in humans and animals, and comprises four subspecies: M. avium subsp. avium (MAA), M. avium subsp. silvaticum (MAS), M. avium subsp. paratuberculosis (MAP), and M. avium subsp. hominissuis (MAH). To improve our understanding of the genetic landscape and diversity of M. avium and its role in disease, we performed a comparative genome analysis of 79 M. avium strains. Our analysis demonstrated that MAH is an open pan-genome species. Phylogenetic analysis based on single nucleotide variants showed that MAH had the highest degree of sequence variability among the subspecies, and MAH strains isolated in Japan and those isolated abroad possessed distinct phylogenetic features. Furthermore, MAP strains, MAS and MAA strains isolated from birds, and many MAH strains that cause the progression of pulmonary disease were grouped in each specific cluster. Comparative genome analysis revealed the presence of genetic elements specific to each lineage, which are thought to be acquired via horizontal gene transfer during the evolutionary process, and identified potential genetic determinants accounting for the pathogenic and host range characteristics of M. avium.

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  • Targeting the miR-200c/LIN28B axis in acquired EGFR-TKI resistance non-small cell lung cancer cells harboring EMT features Reviewed

    Hiroki Sato, Kazuhiko Shien, Shuta Tomida, Kazuhiro Okayasu, Ken Suzawa, Shinsuke Hashida, Hidejiro Torigoe, Mototsugu Watanabe, Hiromasa Yamamoto, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    SCIENTIFIC REPORTS   7   40847   2017.1

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    MicroRNA (miR)-200 family members (miR-200s) are frequently silenced in advanced cancer and have been implicated in the process of epithelial-to-mesenchymal transition (EMT). We previously reported that miR-200s were silenced through promoter methylation in acquired EGFR-tyrosine kinase inhibitor (TKI) resistant non-small cell lung cancer (NSCLC) cells harboring EMT features. In this study, we examined the functional role of miR-200s in NSCLC cells and investigated a novel approach to overcoming acquired EGFR-TKI resistance. In the analysis of NSCLC cell lines, each of the miR-200s expression-silenced cell lines showed promoter methylation. Significant correlations between miR-200c silencing and several oncogenic pathway alterations, including EMT-changes and LIN28B overexpression, were observed in the database analysis. In addition, EGFR-wild type cell lines had lower miR-200s expression levels than EGFR-mutant cell lines. The introduction of miR-200c using pre-miR-200c caused LIN28B suppression in cells with acquired EGFR-TKI resistance that harbored EMT features. Interestingly, both the introduction of miR-200c and the knockdown of LIN28B produced an antitumor effect in acquired EGFR-TKI resistance cells, whereas these manipulations were not effective in parental cells. The miR-200c/LIN28B axis plays an important role in cells with acquired resistance to EGFR-TKI that harbor EMT features and might be a useful therapeutic target for overcoming resistance.

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  • Precision Medicine

    Tomida Shuta, Toyooka Shinichi

    Okayama Igakkai Zasshi (Journal of Okayama Medical Association)   129 ( 1 )   59 - 60   2017

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  • Tumor Immune Microenvironment and Nivolumab Efficacy in EGFR Mutation-Positive Non-Small Cell Lung Cancer Based on T790M Status after Disease Progression During EGFR-TKI Treatment. Reviewed

    Haratani K, Hayashi H, Tanaka T, Kaneda H, Togashi Y, Sakai K, Hayashi K, Tomida S, Chiba Y, Yonesaka K, Nonagase Y, Takahama T, Tanizaki J, Tanaka K, Yoshida T, Tanimura K, Takeda M, Yoshioka H, Ishida T, Mitsudomi T, Nishio K, Nakagawa K

    Ann Oncol   28 ( 7 )   1532 - 1539   2017

  • ß-1,3-galactosyl-O-glycosyl-glycoprotein ß-1,6-N-acetylglucosaminyltransferase 3 Increases MCAM Stability, Which Enhances S100A8/A9-Mediated Cancer Motility. Reviewed

    Sumardika IW, Youyi C, Kondo E, Inoue Y, Ruma IMW, Murata H, Kinoshita R, Yamamoto KI, Tomida S, Shien K, Satoh H, Yamauchi A, Futami J, Putranto EW, Hibino T, Toyooka S, Nishibori M, Sakaguchi M

    Oncol Res   2017

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  • Draft Genome Sequence of Probiotic Lactobacillus acidophilus Strain L-55 Isolated from a Healthy Human Gut Reviewed

    Yusuke Fujii, Hidehiro Toh, Takehiro Matsubara, Shuta Tomida, Co Thi Kim Nguyen, Iyo Mimura, Shoji Nakamura, Hidetoshi Morita

    Genome Announcements   4 ( 6 )   2016.12

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    Probiotic
    <italic>Lactobacillus acidophilus</italic>
    L-55 was isolated from a healthy human gut. Here, we report the draft genome sequence of this organism.

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  • Interaction of cytokeratin 19 head domain and HER2 in the cytoplasm leads to activation of HER2-Erk pathway Reviewed

    Tomoaki Ohtsuka, Masakiyo Sakaguchi, Hiromasa Yamamoto, Shuta Tomida, Katsuyoshi Takata, Kazuhiko Shien, Shinsuke Hashida, Tomoko Miyata-Takata, Mototsugu Watanabe, Ken Suzawa, Junichi Soh, Chen Youyi, Hiroki Sato, Kei Namba, Hidejiro Torigoe, Kazunori Tsukuda, Tadashi Yoshino, Shinichiro Miyoshi, Shinichi Toyooka

    SCIENTIFIC REPORTS   6   39557   2016.12

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    HER2 is a receptor tyrosine kinase and its upregulation via activating mutations or amplification has been identified in some malignant tumors, including lung cancers. Because HER2 can be a therapeutic target in HER2-driven malignancies, it is important to understand the molecular mechanisms of HER2 activation. In the current study, we identified that cytokeratin 19 (KRT19) binds to HER2 at the inside face of plasma membrane. HER2 and KRT19, which were concurrently introduced to a human embryonic kidney 293 T cells, revealed an association with each other and resulted in phosphorylation of HER2 with the subsequent activation of a downstream Erk-associated pathway. A binding assay revealed that both the NH2-terminal head domain of KRT19 and the COOH-terminal domain of HER2 were essential for their binding. To investigate the impact of the interaction between HER2 and KRT19 in lung cancer, we examined their expressions and localizations in lung cancers. We found that KRT19 was highly expressed in HER2-positive lung cancer cells, and KRT19 and HER2 were co-localized at the cell membrane. In conclusion, we found that KRT19 intracellularly binds to HER2, playing a critical role in HER2 activation.

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  • NSCLCにおける分子バーコードシークエンス分析による複数の低頻度変異の検出(Detection of multiple low-frequency mutations by molecular-barcode sequencing in NSCLC)

    難波 圭, 冨田 秀太, 枝園 和彦, 鳥越 英次郎, 佐藤 博紀, 山本 寛斉, 宗 淳一, 佃 和憲, 三好 新一郎, 豊岡 伸一

    肺癌   56 ( 6 )   639 - 639   2016.11

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  • Epithelial-to-Mesenchymal Transition Defines Feedback Activation of Receptor Tyrosine Kinase Signaling Induced by MEK Inhibition in KRAS-Mutant Lung Cancer. Reviewed International journal

    Hidenori Kitai, Hiromichi Ebi, Shuta Tomida, Konstantinos V Floros, Hiroshi Kotani, Yuta Adachi, Satoshi Oizumi, Masaharu Nishimura, Anthony C Faber, Seiji Yano

    Cancer discovery   6 ( 7 )   754 - 69   2016.7

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    UNLABELLED: KRAS is frequently mutated in lung cancer. Whereas MAPK is a well-known effector pathway of KRAS, blocking this pathway with clinically available MAPK inhibitors is relatively ineffective. Here, we report that epithelial-to-mesenchymal transition rewires the expression of receptor tyrosine kinases, leading to differential feedback activation of the MAPK pathway following MEK inhibition. In epithelial-like KRAS-mutant lung cancers, this feedback was attributed to ERBB3-mediated activation of MEK and AKT. In contrast, in mesenchymal-like KRAS-mutant lung cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator Sprouty proteins; MEK inhibition led to repression of SPRY4 and subsequent FGFR1-mediated reactivation of MEK and AKT. Therapeutically, the combination of a MEK inhibitor (MEKi) and an FGFR inhibitor (FGFRi) induced cell death in vitro and tumor regressions in vivo These data establish the rationale and a therapeutic approach to treat mesenchymal-like KRAS-mutant lung cancers effectively with clinically available FGFR1 and MAPK inhibitors. SIGNIFICANCE: Adaptive resistance to MEKi is driven by receptor tyrosine kinases specific to the differentiation state of the KRAS-mutant non-small cell lung cancer (NSCLC). In mesenchymal-like KRAS-mutant NSCLC, FGFR1 is highly expressed, and MEK inhibition relieves feedback suppression of FGFR1, resulting in reactivation of ERK; suppression of ERK by MEKi/FGFRi combination results in tumor shrinkage. Cancer Discov; 6(7); 754-69. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 681.

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  • Epidermolysis bullosa simplex with mottled pigmentation with noncicatricial alopecia: identification of a recurrent p.P25L mutation in KRT5 in four affected family members Reviewed

    H. Nagai, N. Oiso, S. Tomida, K. Sakai, S. Fujiwara, Y. Nakamachi, S. Kawano, A. Kawada, K. Nishio, C. Nishigori

    BRITISH JOURNAL OF DERMATOLOGY   174 ( 3 )   633 - 635   2016.3

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  • Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations Reviewed

    Ken Suzawa, Shinichi Toyooka, Masakiyo Sakaguchi, Mizuki Morita, Hiromasa Yamamoto, Shuta Tomida, Tomoaki Ohtsuka, Mototsugu Watanabe, Shinsuke Hashida, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

    Cancer Science   107 ( 1 )   45 - 52   2016.1

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    Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G1 arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations. In this study, we demonstrated the antitumor effect of afatinib, as a HER2-targeted therapy, in lung cancers harboring HER2 alterations in vitro and in vivo. Our results strongly suggest that afatinib is a promising therapeutic option for NSCLC patients with HER2-amplification or mutations.

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  • An Intriguing Correlation Based on the Superimposition of Residue Pairs with Inhibitors that Target Protein-Protein Interfaces Reviewed

    Masakazu Nakadai, Shuta Tomida, Kazuhisa Sekimizu

    SCIENTIFIC REPORTS   6   18543   2016.1

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    Druggable sites on protein-protein interfaces are difficult to predict. To survey inhibitor-binding sites onto which residues are superimposed at protein-protein interfaces, we analyzed publicly available information for 39 inhibitors that target the protein-protein interfaces of 8 drug targets. By focusing on the differences between residues that were superimposed with inhibitors and non-superimposed residues, we observed clear differences in the distances and changes in the solvent-accessible surface areas (.SASA). Based on the observation that two or more residues were superimposed onto inhibitors in 37 (95%) of 39 protein-inhibitor complexes, we focused on the two-residue relationships. Application of a cross-validation procedure confirmed a linear negative correlation between the absolute value of the dihedral angle and the sum of the Delta SASAs of the residues. Finally, we applied the regression equation of this correlation to four inhibitors that bind to new sites not bound by the 39 inhibitors as well as additional inhibitors of different targets. Our results shed light on the two-residue correlation between the absolute value of the dihedral angle and the sum of the Delta SASA, which may be a useful relationship for identifying the key two-residues as potential targets of protein-protein interfaces.

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  • Antitumor effect of afatinib, as a human epidermal growth factor receptor 2-targeted therapy, in lung cancers harboring HER2 oncogene alterations Reviewed

    Ken Suzawa, Shinichi Toyooka, Masakiyo Sakaguchi, Mizuki Morita, Hiromasa Yamamoto, Shuta Tomida, Tomoaki Ohtsuka, Mototsugu Watanabe, Shinsuke Hashida, Yuho Maki, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi

    CANCER SCIENCE   107 ( 1 )   45 - 52   2016.1

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    Human epidermal growth factor receptor 2 (HER2) is a member of the HER family of proteins containing four receptor tyrosine kinases. It plays an important role in the pathogenesis of certain human cancers. In non-small-cell lung cancer (NSCLC), HER2 amplification or mutations have been reported. However, little is known about the benefit of HER2-targeted therapy for NSCLCs harboring HER2 alterations. In this study, we investigated the antitumor effect of afatinib, an irreversible epidermal growth factor receptor (EGFR)-HER2 dual inhibitor, in lung cancers harboring HER2 oncogene alterations, including novel HER2 mutations in the transmembrane domain, which we recently identified. Normal bronchial epithelial cells, BEAS-2B, ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, and G660D) showed constitutive autophosphorylation of HER2 and activation of downstream signaling. They were sensitive to afatinib, but insensitive to gefitinib. Furthermore, we examined the antitumor activity of afatinib and gefitinib in several NSCLC cell lines, and investigated the association between their genetic alterations and sensitivity to afatinib treatment. In HER2-altered NSCLC cells (H2170, Calu-3, and H1781), afatinib downregulated the phosphorylation of HER2 and EGFR as well as their downstream signaling, and induced an antiproliferative effect through G(1) arrest and apoptotic cell death. In contrast, HER2- or EGFR-non-dependent NSCLC cells were insensitive to afatinib. In addition, these effects were confirmed in vivo by using a xenograft mouse model of HER2-altered lung cancer cells. Our results suggest that afatinib is a therapeutic option as a HER2-targeted therapy for NSCLC harboring HER2 amplification or mutations.

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  • トランスレーショナルリサーチ 基礎から臨床応用へ EGFRチロシンキナーゼ阻害剤に対する獲得耐性の機序

    豊岡 伸一, 諏澤 憲, 冨田 秀太, 牧 佑歩, 山本 寛斉, 宗 淳一, 三好 新一郎

    肺癌   55 ( 5 )   359 - 359   2015.10

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  • Small cell lung cancer transformation and T790M mutation: complimentary roles in acquired resistance to kinase inhibitors in lung cancer Reviewed

    Kenichi Suda, Isao Murakami, Kazuko Sakai, Hiroshi Mizuuchi, Shigeki Shimizu, Katsuaki Sato, Kenji Tomizawa, Shuta Tomida, Yasushi Yatabe, Kazuto Nishio, Tetsuya Mitsudomi

    SCIENTIFIC REPORTS   5   14447   2015.9

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    Lung cancers often harbour a mutation in the epidermal growth factor receptor (EGFR) gene. Because proliferation and survival of lung cancers with EGFR mutation solely depend on aberrant signalling from the mutated EGFR, these tumours often show dramatic responses to EGFR tyrosine kinase inhibitors (TKIs). However, acquiring resistance to these drugs is almost inevitable, thus a better understanding of the underlying resistance mechanisms is critical. Small cell lung cancer (SCLC) transformation is a relatively rare acquired resistance mechanism that has lately attracted considerable attention. In the present study, through an in-depth analysis of multiple EGFR-TKI refractory lesions obtained from an autopsy case, we observed a complementary relationship between SCLC transformation and EGFR T790M secondary mutation (resistance mutation). We also identified analogies and differences in genetic aberration between a TKI-refractory lesion with SCLC transformation and one with EGFR T790M mutation. In particular, target sequencing revealed a TP53 P151S mutation in all pre-and post-treatment lesions. PTEN M264I mutation was identified only in a TKI-refractory lesion with SCLC transformation, while PIK3CA and RB1 mutations were identified only in pre-treatment primary tumour samples. These results provide the groundwork for understanding acquired resistance to EGFR-TKIs via SCLC transformation.

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  • An activating ALK gene mutation in ALK IHC-positive/FISH-negative non-small cell lung cancer. Reviewed

    Togashi Y, Mizuuchi H, Kobayashi Y, Hayashi H, Terashima M, Sakai K, Bannno E, Mizukami T, Nakamura Y, de Velasco MA, Fujita Y, Tomida S, Mitsudomi T, Nishio K

    Ann Oncol   26 ( 8 )   1800 - 1801   2015.8

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  • Propionibacterium acnes Strain Populations in the Human Skin Microbiome Associated with Acne Reviewed

    Sorel Fitz-Gibbon, Shuta Tomida, Bor-Han Chiu, Lin Nguyen, Christine Du, Minghsun Liu, David Elashoff, Marie C. Erfe, Anya Loncaric, Jenny Kim, Robert L. Modlin, Jeff F. Miller, Erica Sodergren, Noah Craft, George M. Weinstock, Huiying Li

    JOURNAL OF INVESTIGATIVE DERMATOLOGY   133 ( 9 )   2152 - 2160   2013.9

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    The human skin microbiome has important roles in skin health and disease. However, bacterial population structure and diversity at the strain level is poorly understood. We compared the skin microbiome at the strain level and genome level of Propionibacterium acnes, a dominant skin commensal, between 49 acne patients and 52 healthy individuals by sampling the pilosebaceous units on their noses. Metagenomic analysis demonstrated that although the relative abundances of P. acnes were similar, the strain population structures were significantly different in the two cohorts. Certain strains were highly associated with acne, and other strains were enriched in healthy skin. By sequencing 66 previously unreported P. acnes strains and comparing 71 P. acnes genomes, we identified potential genetic determinants of various P. acnes strains in association with acne or health. Our analysis suggests that acquired DNA sequences and bacterial immune elements may have roles in determining virulence properties of P. acnes strains, and some could be future targets for therapeutic interventions. This study demonstrates a previously unreported paradigm of commensal strain populations that could explain the pathogenesis of human diseases. It underscores the importance of strain-level analysis of the human microbiome to define the role of commensals in health and disease.

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  • Pan-genome and comparative genome analyses of propionibacterium acnes reveal its genomic diversity in the healthy and diseased human skin microbiome. Reviewed

    Tomida S, Nguyen L, Chiu BH, Liu J, Sodergren E, Weinstock GM, Li H

    mBio   4 ( 3 )   e00003 - 13   2013.4

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  • Analysis of Complete Genomes of Propionibacterium acnes Reveals a Novel Plasmid and Increased Pseudogenes in an Acne Associated Strain Reviewed

    Gabriela Kasimatis, Sorel Fitz-Gibbon, Shuta Tomida, Marthew Wong, Huiying Li

    BIOMED RESEARCH INTERNATIONAL   2013   918320   2013

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    The human skin harbors a diverse community of bacteria, including the Gram-positive, anaerobic bacterium Propionibacterium acnes. P. acnes has historically been linked to the pathogenesis of acne vulgaris, a common skin disease affecting over 80% of all adolescents in the US. To gain insight into potential P. acnes pathogenic mechanisms, we previously sequenced the complete genome of a P. acnes strain HL096PA1 that is highly associated with acne. In this study, we compared its genome to the first published complete genome KPA171202. HL096PA1 harbors a linear plasmid, pIMPLE-HL096PA1. This is the first described P. acnes plasmid. We also observed a five-fold increase of pseudogenes in HL096PA1, several of which encode proteins in carbohydrate transport and metabolism. In addition, our analysis revealed a few island-like genomic regions that are unique to HL096PA1 and a large genomic inversion spanning the ribosomal operons. Together, these findings offer a basis for understanding P. acnes virulent properties, host adaptation mechanisms, and its potential role in acne pathogenesis at the strain level. Furthermore, the plasmid identified in HL096PA1 may potentially provide a new opportunity for P. acnes genetic manipulation and targeted therapy against specific disease-associated strains.

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  • Phenotypic and Genomic Analysis of Hypervirulent Human-associated Bordetella bronchiseptica Reviewed

    Umesh Ahuja, Minghsun Liu, Shuta Tomida, Jihye Park, Puneet Souda, Julian Whitelegge, Huiying Li, Eric T. Harvill, Julian Parkhill, Jeff F. Miller

    BMC MICROBIOLOGY   12   167   2012.8

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    Background: B. bronchiseptica infections are usually associated with wild or domesticated animals, but infrequently with humans. A recent phylogenetic analysis distinguished two distinct B. bronchiseptica subpopulations, designated complexes I and IV. Complex IV isolates appear to have a bias for infecting humans; however, little is known regarding their epidemiology, virulence properties, or comparative genomics.
    Results: Here we report a characterization of the virulence of human-associated complex IV B. bronchiseptica strains. In in vitro cytotoxicity assays, complex IV strains showed increased cytotoxicity in comparison to a panel of complex I strains. Some complex IV isolates were remarkably cytotoxic, resulting in LDH release levels in A549 cells that were 10- to 20-fold greater than complex I strains. In vivo, a subset of complex IV strains was found to be hypervirulent, with an increased ability to cause lethal pulmonary infections in mice. Hypercytotoxicity in vitro and hypervirulence in vivo were both dependent on the activity of the bsc T3SS and the BteA effector. To clarify differences between lineages, representative complex IV isolates were sequenced and their genomes were compared to complex I isolates. Although our analysis showed there were no genomic sequences that can be considered unique to complex IV strains, there were several loci that were predominantly found in complex IV isolates.
    Conclusion: Our observations reveal a T3SS-dependent hypervirulence phenotype in human-associated complex IV isolates, highlighting the need for further studies on the epidemiology and evolutionary dynamics of this B. bronchiseptica lineage.

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  • An Expanded Multilocus Sequence Typing Scheme for Propionibacterium acnes: Investigation of 'Pathogenic', 'Commensal' and Antibiotic Resistant Strains Reviewed

    Andrew McDowell, Emma Barnard, Istvan Nagy, Anna Gao, Shuta Tomida, Huiying Li, Anne Eady, Jonathan Cove, Carl E. Nord, Sheila Patrick

    PLOS ONE   7 ( 7 )   e41480   2012.7

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    The Gram-positive bacterium Propionibacterium acnes is a member of the normal human skin microbiota and is associated with various infections and clinical conditions. There is tentative evidence to suggest that certain lineages may be associated with disease and others with health. We recently described a multilocus sequence typing scheme (MLST) for P. acnes based on seven housekeeping genes (http://pubmlst.org/pacnes). We now describe an expanded eight gene version based on six housekeeping genes and two 'putative virulence' genes (eMLST) that provides improved high resolution typing (91eSTs from 285 isolates), and generates phylogenies congruent with those based on whole genome analysis. When compared with the nine gene MLST scheme developed at the University of Bath, UK, and utilised by researchers at Aarhus University, Denmark, the eMLST method offers greater resolution. Using the scheme, we examined 208 isolates from disparate clinical sources, and 77 isolates from healthy skin. Acne was predominately associated with type IA(1) clonal complexes CC1, CC3 and CC4; with eST1 and eST3 lineages being highly represented. In contrast, type IA(2) strains were recovered at a rate similar to type IB and II organisms. Ophthalmic infections were predominately associated with type IA1 and IA2 strains, while type IB and II were more frequently recovered from soft tissue and retrieved medical devices. Strains with rRNA mutations conferring resistance to antibiotics used in acne treatment were dominated by eST3, with some evidence for intercontinental spread. In contrast, despite its high association with acne, only a small number of resistant CC1 eSTs were identified. A number of eSTs were only recovered from healthy skin, particularly eSTs representing CC72 (type II) and CC77 (type III). Collectively our data lends support to the view that pathogenic versus truly commensal lineages of P. acnes may exist. This is likely to have important therapeutic and diagnostic implications.

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  • NKX2-1/TITF1/TTF-1-Induced ROR1 Is Required to Sustain EGFR Survival Signaling in Lung Adenocarcinoma Reviewed

    Tomoya Yamaguchi, Kiyoshi Yanagisawa, Ryoji Sugiyama, Yasuyuki Hosono, Yukako Shimada, Chinatsu Arima, Seiichi Kato, Shuta Tomida, Motoshi Suzuki, Hirotaka Osada, Takashi Takahashi

    CANCER CELL   21 ( 3 )   348 - 361   2012.3

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    We and others previously identified NKX2-1, also known as TITF1 and TTF-1, as a lineage-survival oncogene in lung adenocarcinomas. Here we show that NKX2-1 induces the expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn sustains a favorable balance between prosurvival PI3K-AKT and pro-apoptotic p38 signaling, in part through ROR1 kinase-dependent c-Src activation, as well as kinase activity-independent sustainment of the EGFR-ERBB3 association, ERBB3 phosphorylation, and consequential PI3K activation. Notably, ROR1 knockdown effectively inhibited lung adenocarcinoma cell lines, irrespective of their EGFR status, including those with resistance to the EGFR tyrosine kinase inhibitor gefitinib. Our findings thus identify ROR1 as an "Achilles' heel" in lung adenocarcinoma, warranting future development of therapeutic strategies for this devastating cancer.

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  • MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis Reviewed

    Yasuyuki Hosono, Tomoya Yamaguchi, Eri Mizutani, Kiyoshi Yanagisawa, Chinatsu Arima, Shuta Tomida, Yukako Shimada, Michiyo Hiraoka, Seiichi Kato, Kohei Yokoi, Motoshi Suzuki, Takashi Takahashi

    EMBO JOURNAL   31 ( 2 )   481 - 493   2012.1

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    Cell migration driven by actomyosin filament assembly is a critical step in tumour invasion and metastasis. Herein, we report identification of myosin binding protein H (MYBPH) as a transcriptional target of TTF-1 (also known as NKX2-1 and TITF1), a master regulator of lung development that also plays a role as a lineage-survival oncogene in lung adenocarcinoma development. MYBPH inhibited assembly competence-conferring phosphorylation of the myosin regulatory light chain (RLC) as well as activating phosphorylation of LIM domain kinase (LIMK), unexpectedly through its direct physical interaction with Rho kinase 1 (ROCK1) rather than with RLC. Consequently, MYBPH inhibited ROCK1 and negatively regulated actomyosin organization, which in turn reduced single cell motility and increased collective cell migration, resulting in decreased cancer invasion and metastasis. Finally, we also show that MYBPH is epigenetically inactivated by promoter DNA methylation in a fraction of TTF-1-positive lung adenocarcinomas, which appears to be in accordance with its deleterious functions in lung adenocarcinoma invasion and metastasis, as well as with the paradoxical association of TTF-1 expression with favourable prognosis in lung adenocarcinoma patients. The EMBO Journal (2012) 31, 481-493. doi:10.1038/emboj.2011.416; Published online 15 November 2011

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  • Seven-signal proteomic signature for detection of operable pancreatic ductal adenocarcinoma and their discrimination from autoimmune pancreatitis. Reviewed International journal

    Yanagisawa K, Tomida S, Matsuo K, Arima C, Kusumegi M, Yokoyama Y, Ko SB, Mizuno N, Kawahara T, Kuroyanagi Y, Takeuchi T, Goto H, Yamao K, Nagino M, Tajima K, Takahashi T

    International journal of proteomics   2012   510397 - 510397   2012

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    There is urgent need for biomarkers that provide early detection of pancreatic ductal adenocarcinoma (PDAC) as well as discrimination of autoimmune pancreatitis, as current clinical approaches are not suitably accurate for precise diagnosis. We used mass spectrometry to analyze protein profiles of more than 300 plasma specimens obtained from PDAC, noncancerous pancreatic diseases including autoimmune pancreatitis patients and healthy subjects. We obtained 1063 proteomic signals from 160 plasma samples in the training cohort. A proteomic signature consisting of 7 mass spectrometry signals was used for construction of a proteomic model for detection of PDAC patients. Using the test cohort, we confirmed that this proteomic model had discrimination power equal to that observed with the training cohort. The overall sensitivity and specificity for detection of cancer patients were 82.6% and 90.9%, respectively. Notably, 62.5% of the stage I and II cases were detected by our proteomic model. We also found that 100% of autoimmune pancreatitis patients were correctly assigned as noncancerous individuals. In the present paper, we developed a proteomic model that was shown able to detect early-stage PDAC patients. In addition, our model appeared capable of discriminating patients with autoimmune pancreatitis from those with PDAC.

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  • miR-375 Is Activated by ASH1 and Inhibits YAP1 in a Lineage-Dependent Manner in Lung Cancer Reviewed

    Eri Nishikawa, Hirotaka Osada, Yasumasa Okazaki, Chinatsu Arima, Shuta Tomida, Yoshio Tatematsu, Ayumu Taguchi, Yukako Shimada, Kiyoshi Yanagisawa, Yasushi Yatabe, Shinya Toyokuni, Yoshitaka Sekido, Takashi Takahashi

    CANCER RESEARCH   71 ( 19 )   6165 - 6173   2011.10

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    Lung cancers with neuroendocrine (NE) features are often very aggressive but the underlying molecular mechanisms remain elusive. The transcription factor ASH1/ASCL1 is a master regulator of pulmonary NE cell development that is involved in the pathogenesis of lung cancers with NE features (NE-lung cancers). Here we report the definition of the microRNA miR-375 as a key downstream effector of ASH1 function in NE-lung cancer cells. miR-375 was markedly induced by ASH1 in lung cancer cells where it was sufficient to induce NE differentiation. miR-375 upregulation was a prerequisite for ASH1-mediated induction of NE features. The transcriptional coactivator YAP1 was determined to be a direct target of miR-375. YAP1 showed a negative correlation with miR-375 in a panel of lung cancer cell lines and growth inhibitory activities in NE-lung cancer cells. Our results elucidate an ASH1 effector axis in NE-lung cancers that is functionally pivotal in controlling NE features and the alleviation from YAP1-mediated growth inhibition. Cancer Res; 71(19); 6165-73. (C)2011 AACR.

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  • Proteasomal Non-catalytic Subunit PSMD2 as a Potential Therapeutic Target in Association With Various Clinicopathologic Features in Lung Adenocarcinomas Reviewed

    Yasushi Matsuyama, Motoshi Suzuki, Chinatsu Arima, Qin Miao Huang, Shuta Tomida, Toshiyuki Takeuchi, Ryoji Sugiyama, Yasutomo Itoh, Yasushi Yatabe, Hidemi Goto, Takashi Takahashi

    MOLECULAR CARCINOGENESIS   50 ( 4 )   301 - 309   2011.4

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    We previously identified PSMD2, a subunit of the 19S regulatory complex of proteasomes, as a constituent of a signature associated with the acquisition of metastatic phenotype and poor prognosis in lung cancers. In the present study, we found that knockdown of PSMD2 decreased proteasome activity, and induced growth inhibition and apoptosis in lung cancer cell lines. These effects of siRNA-mediated PSMD2 inhibition were associated with changes in the balance between phosphorylated AKT and p38, as well as with induction of p21. In addition, patients with higher PSMD2 expression had poorer prognosis and a small fraction of lung cancer specimens carried increased copies of PSMD2. Notably, our findings clearly illustrate that lung adenocarcinomas can be divided into two groups; those with and without general upregulation of proteasome pathway genes including PSMD2. This general upregulation was significantly more prevalent in the non-terminal respiratory unit (non-TRU)-type, a recently proposed genetically and clinicopathologically relevant expression profile-defined classification of adenocarcinomas (P &lt; 0.001 by Fisher's exact test). Patients with adenocarcinomas with general upregulation had significantly shorter survival after potentially curative resection (P=0.0001 by log-rank test) independent of disease stage, as shown by multivariate Cox regression analysis. Our results suggest that PSMD2 may be a good molecular target candidate and that other co-regulated proteasome pathway genes and/or their common regulator(s) might also be potential targets, warranting future study including elucidation of the underlying common regulatory mechanism. (C) 2011 Wiley-Liss, Inc.

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  • Novel Metastasis-Related Gene CIM Functions in the Regulation of Multiple Cellular Stress-Response Pathways Reviewed

    Kiyoshi Yanagisawa, Hiroyuki Konishi, Chinatsu Arima, Shuta Tomida, Toshiyuki Takeuchi, Yukako Shimada, Yasushi Yatabe, Tetsuya Mitsudomi, Hirotaka Osada, Takashi Takahashi

    CANCER RESEARCH   70 ( 23 )   9949 - 9958   2010.12

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    Various stresses of the tumor microenvironment produced by insufficient nutrients, pH, and oxygen can contribute to the generation of altered metabolic and proliferative states that promote the survival of metastatic cells. Among many cellular stress-response pathways activated under such conditions are the hypoxia-inducible factor (HIF) pathway and the unfolded protein response (UPR), which is elicited as a response to endoplasmic reticulum (ER) stress. In this study, we report the identification of a novel cancer invasion and metastasis-related gene (hereafter referred to as CIM, also called ERLEC1), which influences both of these stress-response pathways to promote metastasis. CIM was identified by comparing the gene expression profile of a highly metastatic human lung cancer cell line with its weakly metastatic parental clone. We showed that CIM is critical for metastatic properties in this system. Proteomic approaches combined with bioinformatic analyses revealed that CIM has multifaceted roles in controlling the response to hypoxia and ER stress. Specifically, CIM sequestered OS-9 from the HIF-1 alpha complex and PHD2, permitting HIF-1 alpha accumulation by preventing its degradation. Ectopic expression of CIM in lung cancer cells increased their tolerance to hypoxia. CIM also modulated UPR through interaction with the key ER stress protein BiP, influencing cell proliferation under ER stress conditions. Our findings shed light on how tolerance to multiple cellular stresses at a metastatic site can be evoked by an integrated mechanism involving CIM, which can function to coordinate those responses in a manner that promotes metastatic cell survival. Cancer Res; 70(23); 9949-58. (C)2010 AACR.

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  • Regulation of DNA Polymerase POLD4 Influences Genomic Instability in Lung Cancer Reviewed

    Qin Miao Huang, Shuta Tomida, Yuji Masuda, Chinatsu Arima, Ke Cao, Taka-Aki Kasahara, Hirotaka Osada, Yasushi Yatabe, Tomohiro Akashi, Kenji Kamiya, Takashi Takahashi, Motoshi Suzuki

    CANCER RESEARCH   70 ( 21 )   8407 - 8416   2010.11

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    Genomic instability is an important factor in cancer susceptibility, but a mechanistic understanding of how it arises remains unclear. We examined hypothesized contributions of the replicative DNA polymerase delta (pol delta) subunit POLD4 to the generation of genomic instability in lung cancer. In examinations of 158 lung cancers and 5 mixtures of 10 normal lungs, cell cycle- and checkpoint-related genes generally showed mRNA expression increases in cancer, whereas POLD4 showed reduced mRNA in small cell lung cancer (SCLC). A fraction of non-small cell lung cancer patients also showed low expression comparable with that in SCLC, which was associated with poor prognosis. The lung cancer cell line ACC-LC-48 was found to have low POLD4 expression, with higher histone H3K9 methylation and lower acetylation in the POLD4 promoter, as compared with the A549 cell line with high POLD4 expression. In the absence of POLD4, pol delta exhibited impaired in vitro DNA synthesis activity. Augmenting POLD4 expression in cells where it was attenuated altered the sensitivity to the chemical carcinogen 4-nitroquinoline-1-oxide. Conversely, siRNA-mediated reduction of POLD4 in cells with abundant expression resulted in a cell cycle delay, checkpoint activation, and an elevated frequency of chromosomal gap/break formation. Overexpression of an engineered POLD4 carrying silent mutations at the siRNA target site rescued these phenotypes, firmly establishing the role of POLD4 in these effects. Furthermore, POLD4 overexpression reduced intrinsically high induction of gamma-H2AX, a well-accepted marker of double-stranded DNA breaks. Together, our findings suggest that reduced expression of POLD4 plays a role in genomic instability in lung cancer. Cancer Res; 70(21); 8407-16. (C) 2010 AACR.

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  • Erratum: PCNA mono-ubiquitination and activation of translesion DNA polymerases by DNA polymerase α (Journal of Biochemistry (2009) 146:1 (13-21) DOI: 10.1093/jb/mvp043)

    Motoshi Suzuki, Atsuko Niimi, Siripan Limsirichaikul, Shuta Tomida, Qin Miao Huang, Shunji Izuta, Jiro Usukura, Yasutomo Itoh, Takashi Hishida, Tomohiro Akashi, Yoshiyuki Nakagawa, Akihiko Kikuchi, Youri Pavlov, Takashi Murate, Takashi Takahashi

    Journal of Biochemistry   148   261   2010.8

  • Identification of lung cancer metastasis related gene expression profile using combined transcriptome analysis Reviewed

    Kiyoshi Yanagisawa, Shuta Tomida, Takashi Takahashi

    Japanese Journal of Lung Cancer   49 ( 6 )   902 - 909   2009.10

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    While widespread metastasis is the major cause of human lung cancer-related deaths, its underlying mechanism remains largely unclear. Our genome-wide comparison of the expression profiles of a highly metastatic lung cancer cell line, NCI-H460-LNM35 (LNM35), and its parental clone NCI-H460-N15 (N15), resulted in the identification of a cancer metastasis signature composed of 45 genes. Through gene ontology analysis, our study also provided insights into how this 45-gene metastasis signature may contribute to the acquisition of metastatic potential. Furthermore, we were able to show that enforced expression of the DLX4 homeobox gene, which was identified as a gene with significant down-regulation in LNM35 as well as with significant association with favorable prognosis for lung cancer patients, markedly inhibited in vitro motility and invasion as well as in vivo metastasis via both hematogenous and lymphogenous routes. We further identified a novel gene, uncharacterized gene, which is associated with lung cancer metastasis. We confirmed upregulation of its gene expression in a significant fraction of human lung adenocarcinomas cases as well as lung cancer cell lines. Taken together, these findings indicate that our combined transcriptome analysis is an efficient approach to searching for genes possessing both clinical usefulness in terms of prognostic prediction in human cancer cases and clear functional relevance for studying cancer biology in relation to metastasis. © 2009 The Japan Lung Cancer Society.

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  • PCNA Mono-Ubiquitination and Activation of Translesion DNA Polymerases by DNA Polymerase alpha Reviewed

    Motoshi Suzuki, Atsuko Niimi, Siripan Limsirichaikul, Shuta Tomida, Qin Miao Huang, Shunji Izuta, Jiro Usukura, Yasutomo Itoh, Takashi Hishida, Tomohiro Akashi, Yoshiyuki Nakagawa, Akihiko Kikuchi, Youri Pavlov, Takashi Murate, Takashi Takahashi

    JOURNAL OF BIOCHEMISTRY   146 ( 1 )   13 - 21   2009.7

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    Translesion DNA synthesis (TLS) involves PCNA mono-ubiquitination and TLS DNA polymerases (pols). Recent evidence has shown that the mono-ubiquitination is induced not only by DNA damage but also by other factors that induce stalling of the DNA replication fork. We studied the effect of spontaneous DNA replication errors on PCNA mono-ubiquitination and TLS induction. In the pol1L868F strain, which expressed an error-prone pol alpha, PCNA was spontaneously mono-ubiquitinated. Pol alpha L868F had a rate-limiting step at the extension from mismatched primer termini. Electron microscopic observation showed the accumulation of a single-stranded region at the DNA replication fork in yeast cells. For pol alpha errors, pol zeta participated in a generation of +1 frameshifts. Furthermore, in the pol1L868F strain, UV-induced mutations were lower than in the wild-type and a pol delta mutant strain (pol3-5DV), and deletion of the RAD30 gene (pol eta) suppressed this defect. These data suggest that nucleotide misincorporation by pol alpha induces exposure of single-stranded DNA, PCNA mono-ubiquitination and activates TLS pols.

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  • Relapse-Related Molecular Signature in Lung Adenocarcinomas Identifies Patients With Dismal Prognosis Reviewed

    Shuta Tomida, Toshiyuki Takeuchi, Yukako Shimada, Chinatsu Arima, Keitaro Matsuo, Tetsuya Mitsudomi, Yasushi Yatabe, Takashi Takahashi

    JOURNAL OF CLINICAL ONCOLOGY   27 ( 17 )   2793 - 2799   2009.6

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    Purpose
    In order to aid the development of patient-tailored therapeutics, we attempted to identify a relapse-related signature that allows selection of a group of adenocarcinoma patients with a high probability of relapse.
    Patients and Methods
    Whole-genome expression profiles were analyzed in 117 lung adenocarcinoma samples using microarrays consisting of 41,000 probes. A weighted voting classifier for identifying patients with a relapse-related signature was constructed with an approach that allowed no information leakage during each training step, using 10-fold cross-validation and 100 random partitioning procedures.
    Results
    We identified a relapse-related molecular signature represented by 82 probes (RRS-82) through genome-wide expression profiling analysis of a training set of 60 patients. The robustness of RRS-82 in the selection of patients with a high probability of relapse was then validated with a completely blinded test set of 27 adenocarcinoma patients, showing a clear association of high risk RRS-82 with very poor patient prognosis regardless of disease stage. The discriminatory power of RRS-82 was further validated using an additional independent cohort of 30 stage I patients who underwent surgery at a distinct period of time as well as with the Duke data set on a different platform. Furthermore, completely separate training and validation procedures using another data set recently reported by the Director&apos;s Challenge Consortium also successfully confirmed the predictive power of the genes comprising RRS-82.
    Conclusion
    RRS-82 may be useful for identifying adenocarcinoma patients at very high risk for relapse, even those with cancer in the early stage.

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  • Relationship of Deregulated Signaling Converging onto mTOR with Prognosis and Classification of Lung Adenocarcinoma Shown by Two Independent In silico Analyses Reviewed

    Hiromichi Ebi, Shuta Tomida, Toshiyuki Takeuchi, Chinatsu Arima, Takahiko Sato, Tetsuya Mitsudomi, Yasushi Yatabe, Hirotaka Osada, Takashi Takahashi

    CANCER RESEARCH   69 ( 9 )   4027 - 4035   2009.5

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    There is marked disparity with a slight overlap among prognosis-predictive signatures reported thus far for lung cancers. In this study, we aimed at linking poor prognosis with particular pathways and/or functions of the gene sets involved to better understand the underlying molecular characteristics associated with the prognosis of lung adenocarcinomas. Gene set enrichment analysis identified a gene set down-regulated by rapamycin as the most significant, whereas several others responsive to withdrawal of glucose or amino acids, which are related to signaling converging onto mammalian target of rapamycin (mTOR), were also shown to be significantly associated, in addition to those related to DNA damage response and cell cycle progression. We also used connectivity map (C-MAP) analysis, an independent bioinformatics approach, to search for Food and Drug Administration-approved drugs that potentially transform an unfavorable signature to a favorable one. Those results identified inhibitors of phosphatidylinositol 3-kinase (PI3K) and mTOR, as well as unexpected drugs such as phenothiazine antipsychotics and resveratrol as potential candidates. Experimental validation revealed that the latter unexpected agents also inhibited signaling converging onto mTOR and exhibited antitumor activities. In addition, deregulation of multiple signaling converging onto mTOR was shown to be significantly associated with sensitivity to PI-103, a dual specificity PI3K/mTOR inhibitor that is not contained in the C-MAP database, lending further support for the connection. Our results clearly show the existence of gene set-definable, intrinsic heterogeneities in lung adenocarcinomas, which seem to be related to both clinical behavior and sensitivity to agents affecting the identified pathways. [Cancer Res 2009;69(9):4027-35]

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  • Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer Reviewed

    Hirotaka Osada, Shuta Tomida, Yasushi Yatabe, Yoshio Taternatsu, Toshiyuki Takeuchi, Hideki Murakami, Yutaka Kondo, Yoshitaka Sekido, Takashi Takahashi

    CANCER RESEARCH   68 ( 6 )   1647 - 1655   2008.3

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    The proneural basic-helix-loop-helix protein achaete-scute homologue I (ASH1) is expressed in a very limited spectrum of normal and cancerous cells in a lineage-specific manner, including normal pulmonary neuroendocrine cells and lung cancer cells with neuroendocrine features. Our previous results indicated that ASH1 may play a crucial role in the growth and survival of lung cancers with neuroendocrine features, which prompted us to investigate the molecular function of ASH1 in relation to its involvement in carcinogenic processes. Herein, we report for the first time that ASH1 functions as a dual transcription factor by activating neuroendocrine differentiation markers and also repressing putative tumor suppressors. This protein was found to inactivate DKK1 and DKK3, negative regulators of Wnt/beta-catenin signaling, E-cadherin, and integrin 01 through ASH1-mediated deacetylation and repressive trimethylation of lysine 27 (H3K27me3) of histone H3 in the promoter regions of DKK1 and E-cadherin. In addition, ASH1-transduced A549 adenocarcinoma cells exhibited markedly altered morphology characteristics compared with lung cancer cells with neuroendocrine features both in vitro and in vivo and also grew faster in vivo. Our results provide important clues for a better understanding of the molecular and cellular biological roles of ASH1 in the process of carcinogenesis of lung cancers with neuroendocrine features and warrant future investigations to shed light on the lineage-specific dependency of this transcription factor with dual functions.

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  • Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1 Reviewed

    Hisaaki Tanaka, Kiyoshi Yanagisawa, Keiko Shinjo, Ayurnu Taguchi, Ken Maeno, Shuta Tomida, Yukako Shimada, Hirotaka Osada, Takayuki Kosaka, Hideo Matsubara, Tetsuya Mitsudomi, Yoshitaka Sekido, Mitsune Tanimoto, Yasushi Yatabe, Takashi Takahashi

    CANCER RESEARCH   67 ( 13 )   6007 - 6011   2007.7

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    Emerging evidence, although currently very sparse, suggests the presence of "lineage-specific dependency" in the survival mechanisms of certain cancers. TTF-1 has a decisive role as a master regulatory transcription factor in lung development and in the maintenance of the functions of terminal respiratory unit (TRU) cells. We show that a subset of lung adenocarcinoma cell lines expressing TTF-1, which presumably represent those derived from the TRU lineage, exhibit marked dependence on the persistent expression of TTF-1. The inhibition of TTF-1 by RNA interference (RNAi) significantly and specifically induced growth inhibition and apoptosis in these adenocarcinoma cell lines. Furthermore, a fraction of TTF-1-expressing tumors and cell lines displayed an increase in the gene dosage of TTF-1 in the analysis of 214 patients with non-small-cell lung cancer, including 174 adenocarcinomas, showing a tendency of higher frequency of increased gene copies at metastatic sites than at primary sites (P = 0.07, by two-sided Fisher&apos;s exact test). These findings strongly suggest that in addition to the development and maintenance of TRU lineages in normal lung, sustained TTF-1 expression may be crucial for the survival of a subset of adenocarcinomas that express TTF-1, providing credence for the lineage-specific dependency model.

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  • A 25-signal proteomic signature and outcome for patients with resected non-small-cell lung cancer Reviewed

    Kiyoshi Yanagisawa, Shuta Tomida, Yukako Shimada, Yasushi Yatabe, Tetsuya Mitsudomi, Takashi Takahashi

    JOURNAL OF THE NATIONAL CANCER INSTITUTE   99 ( 11 )   858 - 867   2007.6

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    Background Among patients with non-small-cell lung cancer (NSCLC), those with poor prognosis cannot be distinguished from those with good prognosis.
    Methods Matrix-assisted laser desorption-ionization mass spectrometry was used to analyze protein profiles of 174 specimens from NSCLC tumors and 27 specimens from normal lung tissue and to derive a prognosis-associated proteomic signature. Frozen resected tissue specimens were randomly divided into a training set (116 NSCLC and 20 normal lung specimens) and an independent, blinded validation set (58 NSCLC and seven normal lung specimens). Mass spectrometry signals from training set specimens that were differentially associated with specimens from patients with a high risk of recurrence (i.e., who died within 5 years of surgical treatment because of relapse) compared with those from patients with a low risk of recurrence (i.e., alive with no symptoms of relapse after a median follow-up of 89 months) were selected by use of the Fisher's exact test, the Kruskal-Wallis test, and the significance analysis of microarray test. These signals were used to build an individualized, weighted voting-based prognostic signature. The signature was then validated in the independent dataset. Survival was assessed by multivariable Cox regression analysis. Proteins corresponding to individual signals were identified by ion-trap mass spectrometry coupled with high-performance liquid chromatography. All statistical tests were two-sided.
    Results From 2630 mass spectrometry signals from specimens in the training cohort, we derived a signature of 25 signals that was associated with both relapse-free survival and overall survival. Among stage I NSCLC patients in the validation set, the signature was statistically significantly associated with both overall survival (hazard ratio [HR] of death for patients in the high-risk group compared with those in the low-risk group = 61.1, 95% confidence interval [CI] = 8.9 to 419.2, P&lt;.001) and relapse-free survival (HR of relapse = 11.7, 95% CI = 3.1 to 44.8, P&lt;.001). Proteins corresponding to signals in the signature were identified that had various cellular functions, including ribosomal protein L26-like 1, acylphosphatase, and phosphoprotein enriched in astrocytes 15.
    Conclusions We defined a mass spectrometry signature that was associated with survival among NSCLC patients and appeared to distinguish those with poor prognosis from those with good prognosis.

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  • Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors Reviewed

    T Takeuchi, S Tomida, Y Yatabe, T Kosaka, H Osada, K Yanagisawa, T Mitsudomi, T Takahashi

    JOURNAL OF CLINICAL ONCOLOGY   24 ( 11 )   1679 - 1688   2006.4

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    Purpose
    This study was conducted to gain insight into the relationship between expression profiles and underlying genetic changes, which are known to be important for the pathogenesis of lung cancers.
    Methods
    Expression profiles of 18,175 unique genes and three major targets for genetic changes, p53, epidermal growth factor receptor (EGFR, and K-ras, were investigated in 149 patients with non-small-cell lung cancer, including 90 patients with adenocarcinoma to determine their relationships with various clinicopathologic features and Gene Ontology (GO) terms.
    Results
    This study successfully established a basis for expression profile-defined classification, which can classify adenocarcinomas into two major types, terminal respiratory unit (TRU) type and non-TRU type. Our GO term-based identifier of particular biologic processes, molecular functions, and cellular compartments clearly showed characteristic retention of normal peripheral lung features in TRU type, in sharp contrast to the significant association of non-TRU type with cell cycling and proliferation-related features. While significantly higher frequency of EGFR mutation was observed in TRU type, we found that the presence of EGFR mutations was a significant predictor of shorter postoperative survival for TRU type, independent of disease stage. We were also able to identify a set of genes in vivo with significant upregulation in the presence of EGFR mutations.
    Conclusion
    This study has shed light on heterogeneity in lung cancers, especially in adenocarcinomas, by establishing a molecularly, genetically, and clinically relevant, expression profile-defined classification. Future studies using independent patient cohorts are warranted to confirm the prognostic significance of EGFR mutations in TRU-type adenocarcinoma.

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  • A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation Reviewed

    Y Hayashita, H Osada, Y Tatematsu, H Yamada, K Yanagisawa, S Tomida, Y Yatabe, K Kawahara, Y Sekido, T Takahashi

    CANCER RESEARCH   65 ( 21 )   9628 - 9632   2005.11

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    MicroRNAs (miRNAs) are small noncoding RNAs, thought to be involved in physiologic and developmental processes by negatively regulating expression of target genes. We have previously reported frequent down-regulation of the let-7 miRNA family in lung cancers and, in the present study, assessed alteration in a panel of 19 lung cancer cell lines. As a result, we found for the first time that the miR-17-92 cluster, which comprises seven miRNAs and resides in intron 3 of the C13orf25 gene at 13q31.3, is markedly overexpressed in lung cancers, especially with small-cell lung cancer histology. Southern blot analysis revealed the presence of increased gene copy numbers of the miRNA cluster in a fraction of lung cancer cell lines with overexpression. In addition, we were able to show predominant localization of C13orf25 transcripts within the nucleus and introduction of the expression construct of the miR-17-92 cluster, but not the putative open reading frame of C13orf25, enhancing lung cancer cell growth. These findings clearly suggest that marked overexpression of the miR-17-92 cluster with occasional gene amplification may play a role in the development of lung cancers, especially in their most aggressive form, small-cell lung cancer, and that the C13orf25 gene may well be serving as a vehicle in this regard.

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  • Throwing new light on lung cancer pathogenesis: Updates on three recent topics Reviewed

    S Tomida, Y Yatabe, K Yanagisawa, T Mitsudomi, T Takahashi

    CANCER SCIENCE   96 ( 2 )   63 - 68   2005.2

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    Lung cancers have become the leading cause of cancer deaths in Japan, claiming more than 55 000 lives annually. Unfortunately, substantial improvement in terms of cure rates has not been achieved over the last two decades, although during the same period of time in-depth basic knowledge of the molecular mechanisms, which underlies carcinogenesis and progression of this deadly group of neoplasms, has accumulated at an amazing pace. it has consequently become evident that they have many shared but also distinct features, when comparisons are made not only with other common epithelial cancers of adults, such as colon cancer, but also within the various histologic types of lung cancers themselves. This review article provides an up-date on cutting-edge research into the following three different topics, from which important new insights have been obtained. The first concerns genetic instability, especially chromosome instability, and checkpoint failure in lung cancers. Second, we deal with EGFR mutations, which shows revealing specificities in various aspects. Finally, advances in the expression profiling analysis of both transcriptomes and proteomes of lung cancers are summarized.

    DOI: 10.1111/j.1349-7006.2005.00021.x

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  • Reduced expression of Dicer associated with poor prognosis in lung cancer patients Reviewed

    Y Karube, H Tanaka, H Osada, S Tomida, Y Tatematsu, K Yanagisawa, Y Yatabe, J Takamizawa, S Miyoshi, T Mitsudomi, T Takahashi

    CANCER SCIENCE   96 ( 2 )   111 - 115   2005.2

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    Emerging evidence suggests that microRNA, which are well-conserved, abundant and small regulatory RNA, may be involved in the pathogenesis of human cancers. We recently reported that expression of let-7 was frequently reduced in lung cancers, and that reduced let-7 expression was significantly associated with shorter patient survival. Two members of the double-stranded RNA-specific endonuclease family, Dicer and Drosha, convert precursor forms of microRNA into their mature forms using a stepwise process. In the present study, we examined expression levels of these genes in 67 non-small cell lung cancer cases, and found for the first time that Dicer expression levels were reduced in a fraction of lung cancers with a significant prognostic impact on the survival of surgically treated cases. It should be noted that multivariate COX regression analysis showed that the prognostic impact of Dicer (P = 0.001) appears to be independent of disease stage (P = 0.001), while logistic regression analysis demonstrated that the higher incidence of reduced Dicer expression in poorly differentiated tumors remained significant even after correction for other parameters (P = 0.02). Given the fundamental and multiple biological roles of Dicer in various cellular processes, our results suggest the involvement of reduced Dicer expression in the development of lung cancers, thus warranting further investigations of the underlying mechanisms, which can be expected to enhance understanding of the molecular pathogenesis of this fatal cancer.

    DOI: 10.1111/j.1349-7006.2005.00015.x

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  • Artificial neural network approach for selection of susceptible single nucleotide polymorphisms and construction of prediction model on childhood allergic asthma Reviewed

    Y Tomita, S Tomida, Y Hasegawa, Y Suzuki, T Shirakawa, T Kobayashi, H Honda

    BMC BIOINFORMATICS   5   120   2004.9

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    Background: Screening of various gene markers such as single nucleotide polymorphism ( SNP) and correlation between these markers and development of multifactorial disease have previously been studied. Here, we propose a susceptible marker-selectable artificial neural network ( ANN) for predicting development of allergic disease.
    Results: To predict development of childhood allergic asthma (CAA) and select susceptible SNPs, we used an ANN with a parameter decreasing method (PDM) to analyze 25 SNPs of 17 genes in 344 Japanese people, and select 10 susceptible SNPs of CAA. The accuracy of the ANN model with 10 SNPs was 97.7% for learning data and 74.4% for evaluation data. Important combinations were determined by effective combination value (ECV) defined in the present paper. Effective 2-SNP or 3-SNP combinations were found to be concentrated among the 10 selected SNPs.
    Conclusion: ANN can reliably select SNP combinations that are associated with CAA. Thus, the ANN can be used to characterize development of complex diseases caused by multiple factors. This is the first report of automatic selection of SNPs related to development of multifactorial disease from SNP data of more than 300 patients.

    DOI: 10.1186/1471-2105-5-120

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  • Gene expression-based, individualized outcome prediction for surgically treated lung cancer patients Reviewed

    S Tomida, K Koshikawa, Y Yatabe, T Harano, N Ogura, T Mitsudomi, M Some, K Yanagisawa, T Takahashi, H Osada, T Takahashi

    ONCOGENE   23 ( 31 )   5360 - 5370   2004.7

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    Individualized outcome prediction classifiers were successfully constructed through expression pro. ling of a total of 8644 genes in 50 non-small-cell lung cancer (NSCLC) cases, which had been consecutively operated on within a defined short period of time and followed up for more than 5 years. The resultant classifier of NSCLCs yielded 82% accuracy for forecasting survival or death 5 years after surgery of a given patient. In addition, since two major histologic classes may differ in terms of outcome-related expression signatures, histologic-type-specific outcome classifiers were also constructed. The resultant highly predictive classifiers, designed specifically for nonsquamous cell carcinomas, showed a prediction accuracy of more than 90% independent of disease stage. In addition to the presence of heterogeneities in adenocarcinomas, our unsupervised hierarchical clustering analysis revealed for the first time the existence of clinicopathologically relevant subclasses of squamous cell carcinomas with marked differences in their invasive growth and prognosis. This finding clearly suggests that NSCLCs comprise distinct subclasses with considerable heterogeneities even within one histologic type. Overall, these findings should advance not only our understanding of the biology of lung cancer but also our ability to individualize postoperative therapies based on the predicted outcome.

    DOI: 10.1038/sj.onc.1207697

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  • Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival Reviewed

    J Takamizawa, H Konishi, K Yanagisawa, S Tomida, H Osada, H Endoh, T Harano, Y Yatabe, M Nagino, Y Nimura, T Mitsudomi, T Takahashi

    CANCER RESEARCH   64 ( 11 )   3753 - 3756   2004.6

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    In this study, we report for the first time reduced expression of the let-7 microRNA in human lung cancers. Interestingly, 143 lung cancer cases that had undergone potentially curative resection could be classified into two major groups according to let-7 expression in unsupervised hierarchical analysis, showing significantly shorter survival after potentially curative resection in cases with reduced let-7 expression (P = 0.0003). Multivariate COX regression analysis showed this prognostic impact to be independent of disease stage (hazard ratio = 2.17; P = 0.009). In addition, overexpression of let-7 in A549 lung adenocarcinoma cell line inhibited lung cancer cell growth in vitro. This study represents the first report of reduced expression of let-7 and the potential clinical and biological effects of such a microRNA alteration.

    DOI: 10.1158/0008-5472.CAN-04-0637

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  • Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time reverse transcriptase polymerase chain reaction Reviewed

    H Endoh, S Tomida, Y Yatabe, H Konishi, H Osada, K Tajima, T Kuwano, T Takahashi, T Mitsudomi

    JOURNAL OF CLINICAL ONCOLOGY   22 ( 5 )   811 - 819   2004.3

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    Purpose Recently, several expression-profiling experiments have shown that adenocarcinoma can be classified into subgroups that also reflect patient survival. In this study, we examined the expression patterns of 44 genes selected by these studies to test whether their expression patterns were relevant to prognosis in our cohort as well, and to create a prognostic model applicable to clinical practice,
    Patients and Methods Expression levels were determined in 85 adenocarcinoma patients by quantitative reverse transcriptase polymerase chain reaction. Cluster analysis was performed, and a prognostic model was created by the proportional hazards model using a stepwise method.
    Results Hierarchical clustering divided the cases into three major groups, and group B, comprising 21 cases, had significantly poor survival (P = .0297). Next, we tried to identify a smaller number of genes of particular predictive value, and eight genes (PTK7, CIT, SCNN1A, PGES, ERO1L, ZWINT, and two ESTs) were selected. We then calculated a risk index that was defined as a linear combination of gene expression values weighted by their estimated regression coefficients. The risk index was a significant independent prognostic factor (P = .0021) by multivariate analysis. Furthermore, the robustness of this model was confirmed using an independent set of 21 patients (P = .0085).
    Conclusion By analyzing a reasonably small number of genes, patients with adenocarcinoma could be stratified according to their prognosis. The prognostic model could be applicable to future decisions concerning treatment.
    (C) 2004 by American Society of Clinical Oncology.

    DOI: 10.1200/JCO.2004.04.109

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  • Inference of common genetic network using fuzzy adaptive resonance theory associated matrix method Reviewed

    H Takahashi, S Tomida, T Kobayashi, H Honda

    JOURNAL OF BIOSCIENCE AND BIOENGINEERING   96 ( 2 )   154 - 160   2003.8

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    Inferring genetic networks from gene expression data is the most challenging work in the postgenomic era. However, most studies tend to show their genetic network inference ability by using artificial data. Here, we developed the fuzzy adaptive resonance theory associated matrix (F-ART matrix) method to infer genetic networks and applied it to experimental time series data, which are gene expression profiles of Saccharomyces cerevisiae responding under oxidative stresses such as diamide, heat shock and H2O2. We preprocessed them using the fuzzy adaptive resonance theory and successfully identified genetic interactions by drawing a 2-dimensional matrix. The identified interactions between diamide and heat shock stress were confirmed to be the common interactions for two stresses, compared with the KEGG metabolic map, BRITE protein interaction map, and gene interaction data of other papers. In the predicted common genetic network, the hit ratio was 60% for the KEGG map. Several gene interactions were also drawn, which have been reported to be important in oxidative stress. This result suggests that F-ART matrix has the potential to function as a new method to extract the common genetic networks of two different stresses using experimental time series microarray data.

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  • Analysis of expression profile using fuzzy adaptive resonance theory Reviewed

    S Tomida, T Hanai, H Honda, T Kobayashi

    BIOINFORMATICS   18 ( 8 )   1073 - 1083   2002.8

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    Motivation: It is well understood that the successful clustering of expression profiles give beneficial ideas to understand the functions of uncharacterized genes. In order to realize such a successful clustering, we investigate a clustering method based on adaptive resonance theory (ART) in this report.
    Results: We apply Fuzzy ART as a clustering method for analyzing the time series expression data during sporulation of Saccharomyces cerevisiae. The clustering result by Fuzzy ART was compared with those by other clustering methods such as hierarchical clustering, k-means algorithm and self-organizing maps (SOMs). In terms of the mathematical validations, Fuzzy ART achieved the most reasonable clustering. We also verified the robustness of Fuzzy ART using noised data. Furthermore, we defined the correctness ratio of clustering, which is based on genes whose temporal expressions are characterized biologically. Using this definition, it was proved that the clustering ability of Fuzzy ART was superior to other clustering methods such as hierarchical clustering, k-means algorithm and SOMs. Finally, we validate the clustering results by Fuzzy ART in terms of biological functions and evidence.

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  • Artificial neural network predictive model for allergic disease using single nucleotide polymorphisms data Reviewed

    S Tomida, T Hanai, N Koma, Y Suzuki, T Kobayashi, H Honda

    JOURNAL OF BIOSCIENCE AND BIOENGINEERING   93 ( 5 )   470 - 478   2002.5

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    The purpose of this study was to develop a novel diagnostic prediction method for allergic diseases from the data of single nucleotide polymorphisms (SNPs) using an artificial neural network (ANN). We applied the prediction method to four allergic diseases, such as atopic dermatitis (AD), allergic conjunctivitis (AC), allergic rhinitis (AR) and bronchial asthma (BA), and verified its predictive ability. Almost all the learning data were precisely predicted. Regarding the evaluation data, the learned ANN model could correctly predict a diagnosis with more than 78% accuracy. We also analyzed the SNP data using multiple regression analysis (MRA). Using the MRA model, less than 10% of patients with the above allergic diseases were correctly diagnosed, while this figure was more than 75% for persons without allergic diseases. From these results, it was shown that the ANN model was superior to the MRA model with respect to predictive ability of allergic diseases. Moreover, we used two different methods to convert the genetic polymorphism data into numerical data. Using both methods, diagnostic predictions were quite precise and almost the same predictive abilities were observed. This is the first study showing the application and usefulness of an ANN for the prediction of allergic diseases based on SNP data.

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  • Genetic Network Analysis Using F2DMatrix

    Takahashi Hiro, Tomida Shuta, Kobayashi Takeshi, Honda Hiroyuki

    GI   13   377 - 379   2002

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    DOI: 10.11234/gi1990.13.377

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  • Determination of operating conditions in activated sludge process using fuzzy neural network and genetic algorithm Reviewed

    H Yoshikawa, T Hanai, S Tomida, H Honda, T Kobayashi

    JOURNAL OF CHEMICAL ENGINEERING OF JAPAN   34 ( 8 )   1033 - 1039   2001.8

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    In order to realize control of activated sludge process, a simulation model for effluent chemical oxygen demand (COD) was constructed using the time series data of three months. Here, the recursive fuzzy neural network (RFNN) was applied for the simulation. The simulation model could estimate effluent COD value with relatively high accuracy (average error: 0.68 mg/l). Next, to control effluent COD value to the desirable level, the search system for the values of the control variables, dissolved oxygen concentration (DO) and mixed liquor suspended solid (MLSS), was constructed using the genetic algorithm (GA) and GA with the reliability index (R1), called as RIGA. In search for DO and MLSS values, accuracy of GA search system was high (average error: 0.16 mg/l for DO and 214 mg/l for MLSS) and accuracy of RIGA search system was higher than GA (average error: 0.11 mg/l for DO and 144 mg/l for MLSS). Then, the search using RIGA was further extended for one-year data to check the ability of this system. As a result, the constructed system could search DO and MLSS values with the average errors of 0.10 mg/l and 162 mg/l, respectively.

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  • A simulation model for activated sludge process using fuzzy neural network Reviewed

    T Hanai, S Tomida, H Honda, T Kobayashi

    ARTIFICIAL NEURAL NETWORKS IN MEDICINE AND BIOLOGY   253 - 258   2000

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    In order to construct a simulation model for estimating the effluent chemical oxygen demand (COD) value of an activated sludge process in a "U" plant, fuzzy neural network (FNN) was applied. The constructed FNN model could simulate periodic changes in COD with high accuracy. Comparing the simulation result obtained using the FNN model with that obtained using the multiple regression analysis (MRA) model, it was found that the FNN model had 3.7 times lower error than the MRA model. The FNN models corresponding to each of the four seasons were also constructed. Analyzing the fuzzy rules acquired from the FNN models after learning, the operational characteristic of this plant could be elucidated.

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Books

  • 実験医学(増刊)・皮膚細菌叢のバイオロジー

    冨田 秀太( Role: Contributor)

    羊土社  2014 

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  • Trends in skin microbiome

    TOMIDA Shuta( Role: Contributor)

    Shujunsha  2013.11 

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  • 実験医学(増刊)・皮膚のマイクロバイオーム研究最前線

    冨田 秀太( Role: Contributor)

    羊土社  2013 

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  • 実験医学(増刊)・ 発現プロファイル解析に基づく肺癌の診断・治療の新展開

    羊土社  2004 

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MISC

  • がん遺伝子パネル検査で検出されたPGPVの特性および遺伝子医療部門への介入方法の検討

    十川 麗美, 山本 英喜, 河内 麻里子, 二川 摩周, 加藤 芙美乃, 蓮岡 佳代子, 遠西 大輔, 冨田 秀太, 平沢 晃

    日本遺伝カウンセリング学会誌   43 ( 2 )   77 - 77   2022.6

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    Language:Japanese   Publisher:(一社)日本遺伝カウンセリング学会  

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  • Genomic medicine and new treatment strategies based on biomarkers for soft tissue sarcoma

    中田英二, 藤原智洋, 国定俊之, 尾崎敏文, 平沢晃, 二川摩周, 遠西大輔, 冨田秀太, 久保寿夫, 宮本理史

    整形・災害外科   65 ( 3 )   2022

  • プレシジョン・メディシンの時代に呼吸器外科医が果たす役割

    枝園和彦, 枝園和彦, 諏澤憲, 山本寛斉, 岡崎幹生, 田中真, 三好健太郎, 杉本誠一郎, 遠西大輔, 冨田秀太, 豊岡伸一

    日本呼吸器外科学会総会(Web)   39th   2022

  • がんゲノム医療と肺がん

    豊岡伸一, 蓮岡佳代子, 久保寿夫, 遠西大輔, 冨田秀太

    日本肺癌学会学術集会号   62nd (CD-ROM)   2021

  • 胆・膵癌におけるがん遺伝子パネル検査の課題-細胞診にできること-

    井上博文, 井上博文, 井上博文, 松岡博美, 實平悦子, 松岡昌志, 冨田秀太, 松本和幸, 堀口繁, 加藤博也, 山本英喜, 山本英喜, 柳井広之, 平沢晃

    日本臨床細胞学会雑誌(Web)   60   2021

  • がんゲノム医療で見つかるPGPVsの特徴

    十川麗美, 山本英喜, 山本英喜, 河内麻里子, 二川摩周, 浦川優作, 遠西大輔, 冨田秀太, 平沢晃, 平沢晃, 平沢晃

    日本癌学会学術総会抄録集(Web)   80th   2021

  • 肉腫におけるがん遺伝子パネルによる融合遺伝子の検出

    中田英二, 国定俊之, 藤原智洋, 遠西大輔, 冨田秀太, 尾崎敏文, 尾崎敏文

    中部日本整形外科災害外科学会雑誌   64 ( 秋季学会 )   107 - 107   2021

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    J-GLOBAL

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  • 最良のホルマリン固定パラフィン切片の条件と病理組織像からの核酸収量予測システム

    井上博文, 井上博文, 井上博文, 冨田秀太

    日本癌学会学術総会抄録集(Web)   80th   2021

  • がんゲノム医療におけるPGPVに対する遺伝子医療部門の取り組み

    十川麗美, 河内麻里子, 二川摩周, 加藤芙美乃, 蓮岡佳代子, 浦川優作, 坂井美佳, 坂井美佳, 山本英喜, 山本英喜, 遠西大輔, 冨田秀太, 平沢晃, 平沢晃, 平沢晃

    日本遺伝性腫瘍学会学術集会プログラム・抄録集   27th   2021

  • Practice and report of genetic education using videos

    十川麗美, 山下範之, 河内麻里子, 二川摩周, 加藤芙美乃, 浦川優作, 山本英喜, 山本英喜, 冨田秀太, 平沢晃, 平沢晃

    日本遺伝カウンセリング学会誌   42 ( 2 )   2021

  • The activation of YES1 leads to the acquired resistance to neratinib in HER2-amplified breast and lung cancers

    Hiromasa Yamamoto, Tatsuaki Takeda, Ken Suzawa, Shuta Tomida, Shunsaku Miyauchi, Kota Araki, Kentaro Nakata, Akihiro Miura, Tadahiko Shien, Yoshihisa Kitamura, Toshiaki Sendo, Shinichi Toyooka

    CANCER RESEARCH   80 ( 16 )   2020.8

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    Language:English   Publishing type:Research paper, summary (international conference)   Publisher:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2020-1884

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  • Impact of EGFR-TKI Treatment on the Tumor Immune Microenvironment in EGFR Mutation-Positive Non-Small Cell Lung Cancer. International journal

    Kohsuke Isomoto, Koji Haratani, Hidetoshi Hayashi, Shigeki Shimizu, Shuta Tomida, Takashi Niwa, Toshihide Yokoyama, Yasushi Fukuda, Yasutaka Chiba, Ryoji Kato, Junko Tanizaki, Kaoru Tanaka, Masayuki Takeda, Takashi Ogura, Tadashi Ishida, Akihiko Ito, Kazuhiko Nakagawa

    Clinical cancer research : an official journal of the American Association for Cancer Research   26 ( 8 )   2037 - 2046   2020.4

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    PURPOSE: The impact of EGFR tyrosine kinase inhibitors (TKI) on the tumor immune microenvironment (TME) in non-small cell lung cancer (NSCLC) is unclear. EXPERIMENTAL DESIGN: We retrospectively identified 138 patients with EGFR-mutated NSCLC who underwent rebiopsy after progression during EGFR-TKI treatment. PD-L1 and CD73 expression in tumor cells and tumor-infiltrating lymphocyte (TIL) density at baseline and after progression were determined by IHC. Tumor mutation burden (TMB) was determined by next-generation sequencing. RESULTS: The proportion of patients with a PD-L1 expression level of ≥50% (high) increased from 14% before to 28% after EGFR-TKI (P = 0.0010). Whereas CD8+ and FOXP3+ TIL densities were significantly lower after EGFR-TKI treatment than before, CD8+ TIL density was maintained in tumors with a high PD-L1 expression level. Expression of CD73 in tumor cells after EGFR-TKI treatment was higher than that before in patients with a high PD-L1 expression level. TMB tended to be higher after EGFR-TKI treatment than before (3.3→4.1 mutations/Mbp, P = 0.0508). Median progression-free survival for subsequent treatment with antibodies to PD-1 was longer for patients with a high than for those with a low PD-L1 expression after EGFR-TKI (7.1 vs. 1.7 months, P = 0.0033), and two of five patients whose PD-L1 expression level changed from low to high after EGFR-TKI treatment achieved a PFS of >6 months. CONCLUSIONS: EGFR-TKI treatment was associated with changes in the TME of EGFR-mutated NSCLC, and such changes may provide clues for optimization of subsequent PD-1 inhibitor treatment.

    DOI: 10.1158/1078-0432.CCR-19-2027

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  • がんゲノム医療外来で遺伝性腫瘍が疑われた症例に関する詳細と当院の取り組み

    十川麗美, 河内麻里子, 二川摩周, 加藤芙美乃, 蓮岡佳代子, 浦川優作, 坂井美佳, 山本英喜, 山本英喜, 遠西大輔, 冨田秀太, 平沢晃, 平沢晃, 十川麗美

    日本人類遺伝学会大会プログラム・抄録集   65th (CD-ROM)   2020

  • がん遺伝子パネル検査受検を契機にHBOCが判明し本人および血縁者介入につながった一例

    十川麗美, 小川千加子, 蓮岡佳代子, 冨田秀太, 井上博文, 松原岳大, 二川摩周, 浦川優作, 河内麻里子, 河内麻里子, 山本英喜, 増山寿, 平沢晃, 平沢晃

    日本遺伝性腫瘍学会学術集会プログラム・抄録集   26th   2020

  • がんゲノム医療に順応する細胞診検査体制~Rapid on-site evaluation:ROSEへの対応~

    井上博文, 井上博文, 松岡博美, 實平悦子, 松岡昌志, 冨田秀太, 平沢晃, 柳井広之

    日本臨床細胞学会雑誌(Web)   59   2020

  • Practical impacts of multi-gene cancer profiling on cancer precision medicine and hereditary tumor

    山本英喜, 山本英喜, 久保寿夫, 冨田秀太, 遠西大輔, 豊岡伸一, 豊岡伸一, 平沢晃

    日本癌学会学術総会抄録集(Web)   79th   2020

  • ゲノム医療におけるエキスパートパネル【がんゲノム医療中核拠点病院でのエキスパートパネル】岡山大学のエキスパートパネル

    柳井広之, 都地友紘, 谷口恒平, 西田賢司, 井上博文, 井上博文, 松岡博美, 平沢晃, 平沢晃, 河内麻里子, 河内麻里子, 山本英喜, 山本英喜, 冨田秀太, 冨田秀太, 遠西大輔

    病理と臨床   38 ( 6 )   2020

  • 腫瘍免疫と微小環境 EGFRチロシンキナーゼ阻害薬のEGFR遺伝子変異陽性進行非小細胞肺癌の腫瘍微小環境への影響

    磯本 晃佑, 原谷 浩司, 林 秀敏, 清水 重喜, 富田 秀太, 丹羽 崇, 横山 俊秀, 福田 泰, 千葉 康敬, 加藤 了資, 谷崎 潤子, 田中 薫, 武田 真幸, 小倉 高志, 石田 直, 伊藤 彰彦, 中川 和彦

    肺癌   59 ( 6 )   567 - 567   2019.11

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  • EGFRチロシンキナーゼ阻害薬のEGFR遺伝子変異陽性進行非小細胞肺癌のPD-L1発現率への影響

    磯本 晃佑, 原谷 浩司, 林 秀敏, 清水 重喜, 冨田 秀太, 丹羽 崇, 横山 俊秀, 福田 泰, 千葉 康敬, 加藤 了資, 谷崎 潤子, 田中 薫, 武田 真幸, 小倉 高志, 石田 直, 伊藤 彰彦, 中川 和彦

    肺癌   59 ( 4 )   419 - 419   2019.8

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  • Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden. Reviewed International journal

    Makimoto G, Ohashi K, Tomida S, Nishii K, Matsubara T, Kayatani H, Higo H, Ninomiya K, Sato A, Watanabe H, Kano H, Ninomiya T, Kubo T, Rai K, Ichihara E, Hotta K, Tabata M, Toyooka S, Takata M, Maeda Y, Kiura K

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer   14 ( 11 )   2009 - 2018   2019.7

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    INTRODUCTION: The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. METHODS: Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction. RESULTS: ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes. CONCLUSIONS: High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.

    DOI: 10.1016/j.jtho.2019.07.017

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  • Rapid acquired resistance to alectinib in ALK-positive lung cancers with high tumor mutation burden

    Kadoaki Ohashi, Go Makimoto, Shuta Tomida, Kazuya Nishii, Shinichi Toyooka, Katsuyuki Kiura

    CANCER RESEARCH   79 ( 13 )   2019.7

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    DOI: 10.1158/1538-7445.AM2019-752

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  • 肺がんゲノム医療の経験と今後の展望

    諏澤憲, 久保寿夫, 冨田秀太, 高橋優太, 枝園和彦, 山本寛斉, 遠西大輔, 田端雅弘, 木浦勝行, 豊岡伸一

    日本臨床腫瘍学会学術集会(CD-ROM)   17th   2019

  • リキッドバイオプシーでBRCA1の生殖細胞系列病的バリアントが示唆され遺伝カウンセリングを通じて確定診断に至った一例

    十川麗美, 小川千加子, 蓮岡佳代子, 冨田秀太, 井上博文, 松原岳大, 二川摩周, 江見裕美, 浦川優作, 河内麻里子, 河内麻里子, 増山寿, 平沢晃, 平沢晃

    日本人類遺伝学会大会プログラム・抄録集   64th   2019

  • 乳がんにおけるネラチニブ耐性化の機序解析(Analyses of the mechanisms of the resistance to neratinib in breast cancer)

    武田 達明, 山本 寛斉, 冨田 秀太, 高橋 優太, 栗原 英祐, 大越 祐介, 枝園 和彦, 宗 淳一, 北村 佳久, 千堂 年昭, 豊岡 伸一

    日本癌学会総会記事   77回   839 - 839   2018.9

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  • Therapeutic strategy for lung cancer with HER2 alteration

    Shinichi Toyooka, Ken Suzawa, Takashi Ninomiya, Hiromasa Yamamoto, Kazuhiko Shien, Junichi Soh, Shuta Tomida, Katsuyuki Kiura

    CANCER SCIENCE   109   817 - 817   2018.1

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  • Gene expression and mutation profiling for cancer of unknown primary

    Hidetoshi Hayashi, Shuta Tomida, Yoshihiko Fujita, Yosuke Togashi, Kazuko Sakai, Kazuto Nishio, Kazuhiko Nakagawa

    ANNALS OF ONCOLOGY   28   2017.10

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  • 肺癌においてペメトレキセドが次のEGFRチロシンキナーゼ阻害剤治療に及ぼす影響

    小林 祥久, 冨田 秀太, 瀬角 裕一, 富沢 健二, 光冨 徹哉

    日本癌学会総会記事   76回   J - 3057   2017.9

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  • A comprehensive analysis of autopsied specimens and patient-derived cell lines in ALK-positive lung cancers with rapid acquired resistance to alectinib

    Go Makimoto, Kadoaki Ohashi, Kazuya Nishii, Shuta Tomida, Hiroe Kayatani, Tomoki Tamura, Hisao Higo, Kiichiro Ninomiya, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura

    CANCER RESEARCH   77   2017.7

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    DOI: 10.1158/1538-7445.AM2017-3164

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  • Acquired resistance to the third-generation EGFR inhibitor ASP8273 is associated with MET or NRAS gene amplifications in preclinical models

    Kiichiro Ninomiya, Kadoaki Ohashi, Shuta Tomida, Hiroe Kayatani, Tomoki Tamura, Hisao Higo, Go Makimoto, Takashi Ninomiya, Toshio Kubo, Eiki Ichihara, Akiko Sato, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura

    CANCER RESEARCH   77   2017.7

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    DOI: 10.1158/1538-7445.AM2017-3152

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  • Targeting miR-200c/LIN28B Axis in Acquired EGFR-TKI Resistance Non-Small Cell Lung Cancer Cells Harboring EMT Features

    Kazuhiko Shien, Hiroki Sato, Ken Suzawa, Shuta Tomida, Shinsuke Hashida, Hiromasa Yamamoto, Junichi Soh, Hidejiro Torigoe, Kei Namba, Mototsugu Watanabe, Hiroaki Asano, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    JOURNAL OF THORACIC ONCOLOGY   12 ( 1 )   S1267 - S1267   2017.1

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  • Detection of Multiple Low-Frequency Mutations by Molecular-Barcode Sequencing

    Kei Namba, Shuta Tomida, Hidejiro Torigoe, Hiroki Sato, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Kazunori Tsukuda, Shinichiro Miyoshi, Shinichi Toyooka

    JOURNAL OF THORACIC ONCOLOGY   12 ( 1 )   S531 - S531   2017.1

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  • EGFR変異を有する肺癌細胞株における第三世代EGFR-TKI耐性機序の検討

    二宮貴一朗, 大橋圭明, 冨田秀太, 二宮崇, 久保寿夫, 市原英基, 堀田勝幸, 田端雅弘, 谷本光音, 木浦勝行

    日本臨床腫瘍学会学術集会(CD-ROM)   15th   2017

  • 非小細胞肺がんにおける受容体型チロシンキナーゼ遺伝子変異の機能解析

    寺嶋 雅人, 冨樫 庸介, 佐藤 克明, 水内 寛, 坂井 和子, 須田 健一, 中村 雄, 坂野 恵里, 林 秀敏, デベラス・マルコ, 藤田 至彦, 冨田 秀太, 光冨 徹哉, 西尾 和人

    近畿大学医学雑誌   41 ( 3-4 )   20A - 20A   2016.12

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  • 非小細胞肺がんにおける受容体型チロシンキナーゼ遺伝子変異の機能解析

    寺嶋 雅人, 冨樫 庸介, 佐藤 克明, 水内 寛, 坂井 和子, 須田 健一, 中村 雄, 坂野 恵里, 林 秀敏, デベラス・マルコ, 藤田 至彦, 冨田 秀太, 光冨 徹哉, 西尾 和人

    近畿大学医学雑誌   41 ( 3-4 )   20A - 20A   2016.12

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  • Detection of EGFR mutations in circulating cell-free DNA of non-small cell lung cancer patients by next-generation sequencing

    Ken Suzawa, Shuta Tomida, Takahiro Matsubara, Kadoaki Ohashi, Yuho Maki, Hiromasa Yamamoto, Mizuki Morita, Junichi Soh, Hiroaki Asano, Kazunori Tsukuda, Katuyuki Kiura, Shinichiro Miyoshi, Shinichi Toyooka

    CANCER RESEARCH   76   2016.7

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  • 非ビタミンK阻害経口抗凝固薬の有効性と安全性に関する臨床疫学研究

    大島礼子, 小山敏広, 座間味義人, 小川愛子, 森田瑞樹, 冨田秀太, 樋之津史郎, 狩野光伸

    日本計量生物学会年会講演予稿集   2016   41‐46   2016

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  • Afatinib activity against head-and-neck or esophageal squamous cell carcinoma: Significance of activating oncogenic HER4 mutations in head-and-neck squamous cell carcinoma

    Y. Togashi, Y. Nakamura, S. Tomida, H. Hayashi, M. A. de Velasco, K. Sakai, Y. Fujita, S. Hamada, K. Nishio

    ANNALS OF ONCOLOGY   26   97 - 97   2015.12

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  • Integrative algorithm to determine the metastatic carcinoma tissue of origin using next generation sequencing (NGS)

    Hidetoshi Hayashi, Shuta Tomida, Yosuke Togashi, Kazuko Sakai, Yoshihiko Fujita, Junji Tsurutani, Issei Kurahashi, Takayasu Kurata, Kazuhiko Nakagawa, Kazuto Nishio

    ANNALS OF ONCOLOGY   26   86 - 86   2015.11

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  • EGFR and HER2 signals play a salvage role in MEK1-mutated gastric cancer after MEK inhibition

    Takuro Mizukami, Yosuke Togashi, Shunsuke Sogabe, Marco A. de Velasco, Kazuko Sakai, Yoshihiro Fujita, Shuta Tomida, Takako Eguchi Nakajima, Narikazu Boku, Kazuto Nishio

    ANNALS OF ONCOLOGY   26   129 - 129   2015.11

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  • 非小細胞肺がんにおけるDDR2変異の機能解析

    寺嶋 雅人, 冨樫 庸介, 坂井 和子, 佐藤 克明, 須田 健一, 水上 拓郎, 坂野 恵里, 中村 雄, De Velasco Marco, 藤田 至彦, 冨田 秀太, 光冨 徹哉, 西尾 和人

    日本癌学会総会記事   74回   P - 2223   2015.10

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  • 非小細胞肺がんにおけるDDR2変異の機能解析

    寺嶋 雅人, 冨樫 庸介, 坂井 和子, 佐藤 克明, 須田 健一, 水上 拓郎, 坂野 恵里, 中村 雄, De Velasco Marco, 藤田 至彦, 冨田 秀太, 光冨 徹哉, 西尾 和人

    日本癌学会総会記事   74回   P - 2223   2015.10

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  • The diversity and host interactions of Propionibacterium acnes bacteriophages on human skin (vol 9, pg 2092, 2015)

    Jared Liu, Riceley Yan, Qiao Zhong, Sam Ngo, Nathanael J. Bangayan, Lin Nguyen, Timothy Lui, Minghsun Liu, Marie C. Erfe, Noah Craft, Shuta Tomida, Huiying Li

    ISME JOURNAL   9 ( 9 )   2116 - 2116   2015.9

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    DOI: 10.1038/ismej.2015.144

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  • Fibroblast growth factor 9 gene amplification can induce resistance to anti-EGFR therapy in colorectal cancer

    T. Mizukami, Y. Togashi, E. Banno, M. Terashima, M. A. De Velasco, K. Sakai, H. Hayashi, Y. Fujita, S. Tomida, T. Eguchi Nakajima, N. Boku, A. Ito, K. Nakagawa, K. Nishio

    EUROPEAN JOURNAL OF CANCER   51   S46 - S46   2015.9

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  • Clinicopathological and genetic differences between low-grade and high-grade colorectal mucinous adenocarcinoma

    Y. Togashi, Y. Yoshioka, T. Chikugo, M. Terashima, T. Mizukami, H. Hayashi, K. Sakai, M. De Velasco, S. Tomida, Y. Fujita, K. Okuno, K. Nishio

    EUROPEAN JOURNAL OF CANCER   51   S390 - S390   2015.9

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  • Activin signal promotes cancer progression and is involved in cachexia in a subset of pancreatic cancer

    Yosuke Togashi, Akihiro Kogita, Hiroki Sakamoto, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Masayuki Kitano, Masatoshi Kudo, Kazuto Nishio

    CANCER RESEARCH   75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-3402

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  • FGF9 gene amplification can induce resistance to anti-EGFR therapy in colorectal cancer

    Takuro Mizukami, Yosuke Togashi, Eri Banno, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Narikazu Boku, Kazuto Nishio

    CANCER RESEARCH   75   2015.8

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    DOI: 10.1158/1538-7445.AM2015-5456

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  • バイオマーカー探索におけるbioinformaticsの役割

    冨田 秀太, 坂井 和子, 西尾 和人

    がん分子標的治療   13 ( 1 )   113 - 118   2015.4

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    本邦でも急速に普及している次世代シーケンサー(NGS)は、一塩基置換や挿入・欠失といった塩基配列解析のみならず、エクソンレベルの発現解析やバリアントの有無、それらを統合したコピー数解析やリアレンジメントの解析、さらにはエピゲノム解析までを同一プラットフォームで解析することを可能としている。その網羅性・汎用性の高さから、バイオマーカー探索としての利用が進む一方で、蓄積されるデータをいかに解析するかというデータ解析系(ドライ)の問題が最重要課題として認識されつつある。本稿では、今後増加が予想されるNGSを用いたバイオマーカー探索におけるbioinformaticsの役割、特にネットワーク解析について概説する。(著者抄録)

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  • 【ゲノム解析に基づく新しい分子標的治療】 次世代型コンパニオン診断薬の創出を目指したゲノム解析

    冨田 秀太, 坂井 和子, 西尾 和人

    がん分子標的治療   12 ( 4 )   382 - 387   2015.1

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    今日、分子標的薬の開発において、コンパニオン診断薬の同時開発はきわめて重要な課題である。本稿では、(1)FFPEサンプルを対象とした網羅的かつ探索的ながん関連遺伝子変異解析、(2)極微量のサンプルを対象とした既知の遺伝子変異パネルの解析、(3)血液サンプルを対象とした遺伝子変異の(時系列)モニタリング解析に関して概説する。いずれも実用化(臨床応用)された、もしくは実用化間近の解析技術である。これらの解析技術を用いた最新の報告や論文と併せて、次世代型コンパニオン診断薬の創出を目指した最近の動向を概説する。(著者抄録)

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  • Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer

    Yosuke Togashi, Hiroki Sakamoto, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Yoshihiko Fujita, Yasuo Kodera, Kazuko Sakai, Shuta Tomida, Masayuki Kitano, Masatoshi Kudo, Kazuto Nishio

    CANCER RESEARCH   74 ( 19 )   2014.10

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    DOI: 10.1158/1538-7445.AM2014-5271

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  • MEK INHIBITORS ARE EFFECTIVE AGAINST GASTRIC CANCER CELL LINES WITH ONCOGENIC MEK1 GENE MUTATIONS

    Yosuke Togashi, Shunsuke Sogabe, Hiroaki Kato, Masato Terashima, Hidetoshi Hayashi, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Takushi Yasuda, Kazuto Nishio

    ANNALS OF ONCOLOGY   25   2014.10

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    DOI: 10.1093/annonc/mdu435.90

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  • 新規ALK阻害剤であるアレクチニブはMET阻害剤との併用で効果が高まる

    冨樫 庸介, 林 秀敏, 寺嶋 雅人, 坂井 和子, 藤田 至彦, 冨田 秀太, 中川 和彦, 西尾 和人

    肺癌   54 ( 5 )   403 - 403   2014.10

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  • 低酸素はALK融合遺伝子を有するH3122肺癌細胞株のALK阻害剤に対する耐性化を誘導する

    冨樫 庸介, 林 秀敏, 寺嶋 雅人, 坂井 和子, 藤田 至彦, 冨田 秀太, 中川 和彦, 西尾 和人

    肺癌   54 ( 5 )   470 - 470   2014.10

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  • 喫煙によるニコチン曝露はEGFR遺伝子変異陽性肺がんにおいてEGFR-TKIの耐性因子である

    林 秀敏, 冨樫 庸介, 岡本 邦男, 田中 妙, 文田 壮一, 新谷 亮多, 清川 寛文, 坂本 洋一, 寺嶋 雅人, de Velasco Marco A, 坂井 和子, 藤田 至彦, 冨田 秀太, 加藤 元一, 中川 和彦, 西尾 和人

    肺癌   54 ( 5 )   626 - 626   2014.10

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  • 原発性肺癌における受容体型チロシンキナーゼAxlの発現と病理組織学的因子の検討

    佐藤 克明, 清水 重喜, 須田 健一, 水内 寛, 小林 祥久, 下治 正樹, 富沢 健二, 武本 智樹, 岩崎 拓也, 阪口 全宏, 坂井 和子, 冨田 秀太, 西尾 和人, 光冨 徹哉

    肺癌   54 ( 5 )   389 - 389   2014.10

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  • CHRONIC NICOTINE EXPOSURE MEDIATES RESISTANCE TO EGFR-TKI IN EGFR-MUTATED LUNG CANCER VIA EGFR SIGNAL

    Hidetoshi Hayashi, Yosuke Togashi, Kunio Okamoto, Soichi Fumita, Masato Terashima, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Kazuhiko Nakagawa, Kazuto Nishio

    ANNALS OF ONCOLOGY   25   2014.10

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    DOI: 10.1093/annonc/mdu435.122

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  • KIAA1199はグリコーゲンホスホリラーゼキナーゼβサブユニットと結合してグリコーゲンの分解さらには細胞生存を亢進する(KIAA1199 interacts with PHKB and promotes glycogen breakdown and cancer cell survival)

    寺嶋 雅人, 藤田 至彦, 冨樫 庸介, 坂井 和子, 冨田 秀太, 西尾 和人

    日本癌学会総会記事   73回   P - 2211   2014.9

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  • 上皮間葉転換したEGFR-TKI耐性HCC4006におけるABCB1過剰発現は微小管作用薬の交差耐性を誘導する(ABCB1 overexpression in EGFR-TKI resistant HCC4006 cells with EMT feature causes cross-resistant to anti-tubulin agents)

    水内 寛, 須田 健一, 冨田 秀太, 佐藤 克明, 小林 祥久, 下治 正樹, 富沢 健二, 武本 智樹, 岩崎 拓也, 阪口 全宏, 西尾 和人, 光冨 徹哉

    日本癌学会総会記事   73回   E - 1107   2014.9

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  • MEK遺伝子変異を有する胃がんに対するMEK阻害剤の有効性(MEK inhibitor for gastric cancer with MEK1 gene mutations)

    冨樫 庸介, 加藤 寛章, 林 秀敏, 寺嶋 雅人, デベラスコ・マルコ, 坂井 和子, 藤田 至彦, 冨田 秀太, 安田 卓司, 西尾 和人

    日本癌学会総会記事   73回   P - 2349   2014.9

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  • EGFR-TKI獲得耐性の分子生物学的・病理学的進展 T790M変異と小細胞肺癌形質転換(Molecular and pathological evolution in acquisition of resistance to EGFR-TKI-T790M mutation and SCLC transformation)

    須田 健一, 村上 功, 佐藤 克明, 冨田 秀太, 水内 寛, 坂井 和子, 清水 重喜, 富沢 健二, 武本 智樹, 阪口 全宏, 西尾 和人, 谷田部 恭, 光冨 徹哉

    日本癌学会総会記事   73回   E - 1108   2014.9

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  • Serum biomarker analysis of WJOG4107: A randomized phase II trial of adjuvant chemotherapy with S-1 versus CDDP+S-1 for resected stage II-IIIA non-small cell lung cancer (NSCLC).

    Tetsuya Mitsudomi, Yasuo Iwamoto, Shuta Tomida, Kazuko Sakai, Takeharu Yamanaka, Hirohito Tada, Hiroshige Yoshioka, Kazuya Uchino, Ichiro Yoshino, Shunichi Sugawara, Shigeki Mitsuoka, Toshiaki Takahashi, Mitsunori Ohta, Takashi Seto, Shinji Atagi, Morihito Okada, Hideo Saka, Kazuhiko Nakagawa, Yoichi Nakanishi, Kazuto Nishio

    JOURNAL OF CLINICAL ONCOLOGY   32 ( 15 )   2014.5

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  • 【常在細菌叢が操るヒトの健康と疾患】 (第2章)健康を制御する常在細菌叢の新たなバイオロジー 皮膚細菌叢のバイオロジー

    冨田 秀太, 西尾 和人, Li Huiying

    実験医学   32 ( 5 )   739 - 743   2014.3

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    体の表面を覆っている皮膚は最大の臓器であり、頭皮から足の裏まできわめて多様で特徴的な組織を有している。その結果、皮膚の細菌叢(スキンマイクロバイオーム)もそれぞれのニッチに適合した、きわめてユニークなコミュニティーを形成していることが、近年のシーケンス技術の飛躍とともに明らかとなってきた。さらに、皮膚の細菌叢とホスト(宿主)間の相互作用メカニズムが徐々に解明され始めており、今後の展開と新しいメカニズムに基づく治療の可能性が注目を集めている。(著者抄録)

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  • MEK1遺伝子変異を有する胃がん細胞株に対するMEK阻害剤の有効性と臨床サンプルの検討

    冨樫庸介, 曽我部俊介, 加藤寛章, 寺嶋雅人, 林秀敏, 林秀敏, 坂井和子, 藤田至彦, 冨田秀太, 安田卓志, 西尾和人

    日本臨床腫瘍学会学術集会(CD-ROM)   12th   2014

  • 肺癌生物像に基づいた、新しい肺癌治療の戦略 EGFR遺伝子変異を有する肺癌においてβカテニンを阻害することでEGFR-TKIの効果が増強する

    冨樫 庸介, 林 秀敏, 寺嶋 雅人, 藤田 至彦, 坂井 和子, 冨田 秀太, 中川 和彦, 西尾 和人

    肺癌   53 ( 5 )   397 - 397   2013.10

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  • NGSによる極微量検体を用いたmultiplex mutation analysisの最適化(Optimization of multiplex mutation analysis based on minimum amount of lung cancer specimen)

    冨田 秀太, 坂井 和子, 藤田 至彦, 寺嶋 雅人, 富樫 庸介, デベラスコ・マルコ, 光冨 徹哉, 中川 和彦, 西尾 和人

    日本癌学会総会記事   72回   458 - 458   2013.10

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  • 【ゲノム医学・生命科学研究 総集編 ポストゲノムの10年は何をもたらしたか】 (第4章)腸内細菌叢を中心とするマイクロバイオーム 皮膚のマイクロバイオーム研究最前線

    富田 秀太, 西尾 和人, Li Huiying

    実験医学   31 ( 15 )   2527 - 2532   2013.9

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    体の表面を覆っている皮膚は適切な細菌との相互作用を利用することにより、そのバリアとしての機能を維持している器官である。サンプルから直接ゲノムDNAを抽出するメタゲノム解析手法と近年の塩基配列解析技術の著しい向上があいまって、皮膚の細菌叢(スキンマイクロバイオーム)の解明とその機能解析が可能となりつつある。本稿では米国国立衛生研究所(National Institutes of Health:NIH)によるHuman Microbiome Project(HMP)に参加したわれわれの体験を踏まえて、最新のスキンマイクロバイオームの研究を中心に、その現状と今後の展開を紹介する。(著者抄録)

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  • Recent advances in skin microbiome studies

    Experimental Medicine   31 ( 15 )   215 - 220   2013.9

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  • 個別化multiplexの体外診断薬承認に向けて

    坂井和子, 冨田秀太, 光冨徹哉, 中川和彦, 西尾和人

    日本がん分子標的治療学会学術集会プログラム・抄録集   17th   2013

  • miRNAとmRNAの統合解析による肺腺癌の多様性の検討(Combined analysis of miRNA and mRNA expression towards better understanding of heterogeneities in lung adenocarcinoma)

    有馬 千夏, 玉田 嘉紀, 梶野 泰祐, 島田 友香子, 井元 清哉, 冨田 秀太, 宮野 悟, 高橋 隆

    日本癌学会総会記事   71回   254 - 254   2012.8

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  • NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma

    Tomoya Yamaguchi, Kiyoshi Yanagisawa, Ryoji Sugiyama, Yasuyuki Hosono, Yukako Shimada, Chinatsu Arima, Seiichi Kato, Shuta Tomida, Motoshi Suzuki, Hirotaka Osada, Takashi Takahashi

    CLINICAL CANCER RESEARCH   18 ( 10 )   2012.5

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    DOI: 10.1158/1078-0432.MECHRES-PR1

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  • NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma

    Tomoya Yamaguchi, Kiyoshi Yanagisawa, Ryoji Sugiyama, Yasuyuki Hosono, Yukako Shimada, Chinatsu Arima, Seiichi Kato, Shuta Tomida, Motoshi Suzuki, Hirotaka Osada, Takashi Takahashi

    CANCER RESEARCH   72   2012.4

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    DOI: 10.1158/1538-7445.AM2012-LB-17

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  • マイクロRNA発現プロファイルが示す肺腺癌の多様性(miRNA expression profile-defined heterogeneity in lung adenocarcinoma)

    有馬 千夏, 冨田 秀太, 谷田部 恭, 高橋 隆

    日本癌学会総会記事   70回   141 - 141   2011.9

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  • 肺癌におけるPOLD4の関与(Regulation of DNA polymerase subunit POLD4 influences genomic instability in lung cancer)

    鈴木 元, 冨田 秀太, 有馬 千夏, 増田 雄司, 神谷 研二, 長田 啓隆, 谷田部 恭, 高橋 隆

    日本癌学会総会記事   70回   102 - 102   2011.9

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  • MYBPH, a novel transcriptional target of TTF-1/NKX2-1, inhibits ROCK1 and actomyosin assembly, and reduces cell motility and tumor metastasis

    Yasuyuki Hosono, Tomoya Yamaguchi, Eri Mizutan, Kiyoshi Yanagisawa, Chinatsu Arima, Shuta Tomida, Yukako Shimada, Michiyo Hiraoka, Seiichi Kato, Kohei Yokoi, Motoshi Suzuki, Takashi Takahashi

    CANCER RESEARCH   71   2011.4

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    DOI: 10.1158/1538-7445.AM2011-LB-360

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  • Roles of ASH1-miR-375 pathway in development of lung cancers with neuroendocrine features

    Osada Hirotaka, Eri Nishikawa, Chinatsu Arima, Yasumasa Okazaki, Shuta Tomida, Yoshio Tatematsu, Ayumu Taguchi, Yukako Shimada, Kiyoshi Yanagisawa, Shinya Toyokuni, Yoshitaka Sekido, Takashi Takahashi

    CANCER RESEARCH   71   2011.4

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    DOI: 10.1158/1538-7445.AM2011-3992

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  • 肺小細胞癌に見られたPOLD4低発現(Implications of POLD4 regulation and genomic instability in small cell lung cancer)

    鈴木 元, 冨田 秀太, 有馬 千夏, 増田 雄司, 神谷 研二, 長田 啓隆, 谷田部 恭, 黄 勤びょう, 高橋 隆

    日本癌学会総会記事   69回   525 - 525   2010.8

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  • PCNA Mono-Ubiquitination and Activation of Translesion DNA Polymerases by DNA Polymerase alpha (vol 146, pg 13, 2009)

    Motoshi Suzuki, Atsuko Niimi, Siripan Limsirichaikul, Shuta Tomida, Qin Miao Huang, Shunji Izuta, Jiro Usukura, Yasutomo Itoh, Takashi Hishida, Tomohiro Akashi, Yoshiyuki Nakagawa, Akihiko Kikuchi, Youri Pavlov, Takashi Murate, Takashi Takahashi

    JOURNAL OF BIOCHEMISTRY   148 ( 2 )   261 - 261   2010.8

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    DOI: 10.1093/jb/mvq059

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  • バイオインフォマティクス手法を用いた肺癌のトランスクリプトームおよびプロテオーム解析(Bioinformatic analysis of transcriptome and proteome for lung cancer patients)

    冨田 秀太, 柳澤 聖, 衣斐 寛倫, 竹内 俊幸, 有馬 千夏, 松尾 恵太郎, 長田 啓隆, 光冨 徹哉, 谷田部 恭, 高橋 隆

    日本癌学会総会記事   69回   53 - 53   2010.8

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  • 肺腺癌の術後予後の高精度予測を可能とする発現シグネチャーの同定(Relapse-Related Molecular Signature in Lung Adenocarcinomas)

    有馬 千夏, 冨田 秀太, 竹内 俊幸, 島田 友香子, 松尾 恵太郎, 光冨 徹哉, 谷田部 恭, 高橋 隆

    日本癌学会総会記事   68回   454 - 455   2009.8

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  • 新規遺伝子ADw1は上皮細胞間接着に関与し、肺癌で高頻度に発現低下する(ADw1, a novel gene, is frequently inactivated in lung cancer and involved in cell-cell contact)

    長田 啓隆, 立松 義朗, 冨田 秀太, 谷田部 恭, 堀尾 芳嗣, 樋田 豊明, 藤井 万紀子, 村上 秀樹, 近藤 豊, 関戸 好孝, 高橋 隆

    日本癌学会総会記事   67回   298 - 298   2008.9

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  • ASH1 gene may be prototypic "lineagesurvival oncogene" and specific therapeutic target for lung cancers with neuroendocrine features

    Hirotaka Sada, Yoshio Tatematsu, Toshiyuki Takeuchi, Shuta Tomida, Hideki Murakami, Yutaka Kondo, Yasushi Yatabe, Yoshitaka Sekido, Takashi Takahashi

    JOURNAL OF GENE MEDICINE   10 ( 4 )   459 - 459   2008.4

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  • In silico screening of differentially expressed microRNAs in lung cancer

    Shuta Tomida, Koyo Tsujikawa, Takashi Takahashi

    MOLECULAR CANCER THERAPEUTICS   6 ( 12 )   3486S - 3486S   2007.12

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  • 神経内分泌分化誘導因子ASH1によるWntシグナル抑制因子DKK1の発現抑制

    長田 啓隆, 立松 義朗, 竹内 俊幸, 冨田 秀太, 谷田部 恭, 関戸 好孝, 高橋 隆

    日本生化学会大会・日本分子生物学会年会合同大会講演要旨集   80回・30回   3T18 - 4   2007.11

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  • ヒト肺腺癌におけるTTF-1に対するLineage-specific dependencyに関する検討(Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1)

    柳澤 聖, 田中 寿明, 新城 恵子, 田口 歩, 前野 健, 冨田 秀太, 長田 啓隆, 高坂 貴行, 光冨 徹哉, 関戸 好孝, 谷本 光音, 谷田部 恭, 高橋 隆

    日本癌学会総会記事   66回   417 - 417   2007.8

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  • Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1

    Hisaaki Tanaka, Kiyoshi Yanagisawa, Keiko Shinjo, Ayurnu Taguchi, Ken Maeno, Shuta Tomida, Yukako Shimada, Hirotaka Osada, Takayuki Kosaka, Hideo Matsubara, Tetsuya Mitsudomi, Yoshitaka Sekido, Mitsune Tanimoto, Yasushi Yatabe, Takashi Takahashi

    CANCER RESEARCH   67 ( 13 )   6007 - 6011   2007.7

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    Emerging evidence, although currently very sparse, suggests the presence of "lineage-specific dependency" in the survival mechanisms of certain cancers. TTF-1 has a decisive role as a master regulatory transcription factor in lung development and in the maintenance of the functions of terminal respiratory unit (TRU) cells. We show that a subset of lung adenocarcinoma cell lines expressing TTF-1, which presumably represent those derived from the TRU lineage, exhibit marked dependence on the persistent expression of TTF-1. The inhibition of TTF-1 by RNA interference (RNAi) significantly and specifically induced growth inhibition and apoptosis in these adenocarcinoma cell lines. Furthermore, a fraction of TTF-1-expressing tumors and cell lines displayed an increase in the gene dosage of TTF-1 in the analysis of 214 patients with non-small-cell lung cancer, including 174 adenocarcinomas, showing a tendency of higher frequency of increased gene copies at metastatic sites than at primary sites (P = 0.07, by two-sided Fisher&apos;s exact test). These findings strongly suggest that in addition to the development and maintenance of TRU lineages in normal lung, sustained TTF-1 expression may be crucial for the survival of a subset of adenocarcinomas that express TTF-1, providing credence for the lineage-specific dependency model.

    DOI: 10.1158/0008-5472.CAN-06-4774

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  • Identification of a metastasis signature and the DLX4 homeobox protein as a regulator of metastasis by combined transcriptome approach

    S. Tomida, K. Yanagisawa, K. Koshikawa, Y. Yatabe, T. Mitsudomi, H. Osada, T. Takahashi

    ONCOGENE   26 ( 31 )   4600 - 4608   2007.7

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    Although widespread metastasis is the major cause of human lung cancer-related deaths, its underlying mechanism remains largely unclear. Our genome-wide comparison of the expression profiles of a highly metastatic lung cancer cell line, NCI-H460-LNM35 (LNM35), and its parental clone, NCI-H460-N15 (N15), resulted in the identification of a cancer metastasis signature composed of 45 genes. Through gene ontology analysis, our study also provided insights into how this 45-gene metastasis signature may contribute to the acquisition of metastatic potential. By applying the signature to datasets of human cancer cases, we could demonstrate significant associations with a subset of cases with poor prognosis not only for the two datasets of cancers of the lung but also for cancers of the breast. Furthermore, we were able to show that enforced expression of the DLX4 homeobox gene, which was identified as a gene with significant downregulation in LNM35 as well as with significant association with favorable prognosis for lung cancer patients, markedly inhibited in vitro motility and invasion as well as in vivo metastasis via both hematogenous and lymphogenous routes. Taken together, these findings indicate that our combined transcriptome analysis is an efficient approach in the search for genes possessing both clinical usefulness in terms of prognostic prediction in human cancer cases and clear functional relevance for studying cancer biology in relation to metastasis.

    DOI: 10.1038/sj.onc.1210242

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  • A 25-signal proteomic signature and outcome for patients with resected non-small-cell lung cancer

    Kiyoshi Yanagisawa, Shuta Tomida, Yukako Shimada, Yasushi Yatabe, Tetsuya Mitsudomi, Takashi Takahashi

    JOURNAL OF THE NATIONAL CANCER INSTITUTE   99 ( 11 )   858 - 867   2007.6

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    Background Among patients with non-small-cell lung cancer (NSCLC), those with poor prognosis cannot be distinguished from those with good prognosis.
    Methods Matrix-assisted laser desorption-ionization mass spectrometry was used to analyze protein profiles of 174 specimens from NSCLC tumors and 27 specimens from normal lung tissue and to derive a prognosis-associated proteomic signature. Frozen resected tissue specimens were randomly divided into a training set (116 NSCLC and 20 normal lung specimens) and an independent, blinded validation set (58 NSCLC and seven normal lung specimens). Mass spectrometry signals from training set specimens that were differentially associated with specimens from patients with a high risk of recurrence (i.e., who died within 5 years of surgical treatment because of relapse) compared with those from patients with a low risk of recurrence (i.e., alive with no symptoms of relapse after a median follow-up of 89 months) were selected by use of the Fisher's exact test, the Kruskal-Wallis test, and the significance analysis of microarray test. These signals were used to build an individualized, weighted voting-based prognostic signature. The signature was then validated in the independent dataset. Survival was assessed by multivariable Cox regression analysis. Proteins corresponding to individual signals were identified by ion-trap mass spectrometry coupled with high-performance liquid chromatography. All statistical tests were two-sided.
    Results From 2630 mass spectrometry signals from specimens in the training cohort, we derived a signature of 25 signals that was associated with both relapse-free survival and overall survival. Among stage I NSCLC patients in the validation set, the signature was statistically significantly associated with both overall survival (hazard ratio [HR] of death for patients in the high-risk group compared with those in the low-risk group = 61.1, 95% confidence interval [CI] = 8.9 to 419.2, P&lt;.001) and relapse-free survival (HR of relapse = 11.7, 95% CI = 3.1 to 44.8, P&lt;.001). Proteins corresponding to signals in the signature were identified that had various cellular functions, including ribosomal protein L26-like 1, acylphosphatase, and phosphoprotein enriched in astrocytes 15.
    Conclusions We defined a mass spectrometry signature that was associated with survival among NSCLC patients and appeared to distinguish those with poor prognosis from those with good prognosis.

    DOI: 10.1093/jnci/djk197

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  • 肺癌細胞において過剰発現を示すmiRNAクラスター、miR-17-92の同定と機能解析

    林下 陽二, 長田 啓隆, 立松 義郎, 山田 英貴, 柳澤 聖, 冨田 秀太, 谷田部 恭, 川原 克信, 関戸 好孝, 高橋 隆

    日本癌学会総会記事   65回   157 - 157   2006.9

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  • 遺伝子発現プロファイル解析による転移シグネチャーと転移抑制性ホメオボックス遺伝子DLX4の同定

    冨田 秀太, 柳澤 聖, 越川 克己, 谷田部 恭, 光冨 徹哉, 長田 啓隆, 高橋 隆

    日本癌学会総会記事   65回   264 - 264   2006.9

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  • 神経内分泌分化誘導因子ASH1によるWntシグナル抑制因子DKK1の発現抑制

    長田 啓隆, 立松 義朗, 竹内 俊幸, 冨田 秀太, 堀尾 芳嗣, 樋田 豊明, 谷田部 恭, 光冨 徹哉, 関戸 好孝, 高橋 隆

    日本癌学会総会記事   65回   64 - 64   2006.9

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  • Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors

    T Takeuchi, S Tomida, Y Yatabe, T Kosaka, H Osada, K Yanagisawa, T Mitsudomi, T Takahashi

    JOURNAL OF CLINICAL ONCOLOGY   24 ( 11 )   1679 - 1688   2006.4

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    Purpose
    This study was conducted to gain insight into the relationship between expression profiles and underlying genetic changes, which are known to be important for the pathogenesis of lung cancers.
    Methods
    Expression profiles of 18,175 unique genes and three major targets for genetic changes, p53, epidermal growth factor receptor (EGFR, and K-ras, were investigated in 149 patients with non-small-cell lung cancer, including 90 patients with adenocarcinoma to determine their relationships with various clinicopathologic features and Gene Ontology (GO) terms.
    Results
    This study successfully established a basis for expression profile-defined classification, which can classify adenocarcinomas into two major types, terminal respiratory unit (TRU) type and non-TRU type. Our GO term-based identifier of particular biologic processes, molecular functions, and cellular compartments clearly showed characteristic retention of normal peripheral lung features in TRU type, in sharp contrast to the significant association of non-TRU type with cell cycling and proliferation-related features. While significantly higher frequency of EGFR mutation was observed in TRU type, we found that the presence of EGFR mutations was a significant predictor of shorter postoperative survival for TRU type, independent of disease stage. We were also able to identify a set of genes in vivo with significant upregulation in the presence of EGFR mutations.
    Conclusion
    This study has shed light on heterogeneity in lung cancers, especially in adenocarcinomas, by establishing a molecularly, genetically, and clinically relevant, expression profile-defined classification. Future studies using independent patient cohorts are warranted to confirm the prognostic significance of EGFR mutations in TRU-type adenocarcinoma.

    DOI: 10.1200/JCO.2005.03.8224

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  • A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation

    Y Hayashita, H Osada, Y Tatematsu, H Yamada, K Yanagisawa, S Tomida, Y Yatabe, K Kawahara, Y Sekido, T Takahashi

    CANCER RESEARCH   65 ( 21 )   9628 - 9632   2005.11

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    MicroRNAs (miRNAs) are small noncoding RNAs, thought to be involved in physiologic and developmental processes by negatively regulating expression of target genes. We have previously reported frequent down-regulation of the let-7 miRNA family in lung cancers and, in the present study, assessed alteration in a panel of 19 lung cancer cell lines. As a result, we found for the first time that the miR-17-92 cluster, which comprises seven miRNAs and resides in intron 3 of the C13orf25 gene at 13q31.3, is markedly overexpressed in lung cancers, especially with small-cell lung cancer histology. Southern blot analysis revealed the presence of increased gene copy numbers of the miRNA cluster in a fraction of lung cancer cell lines with overexpression. In addition, we were able to show predominant localization of C13orf25 transcripts within the nucleus and introduction of the expression construct of the miR-17-92 cluster, but not the putative open reading frame of C13orf25, enhancing lung cancer cell growth. These findings clearly suggest that marked overexpression of the miR-17-92 cluster with occasional gene amplification may play a role in the development of lung cancers, especially in their most aggressive form, small-cell lung cancer, and that the C13orf25 gene may well be serving as a vehicle in this regard.

    DOI: 10.1158/0008-5472.CAN-05-2352

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  • 網羅的遺伝子発現プロファイリングによる肺癌の個性の描出

    冨田 秀太, 竹内 俊幸, 谷田部 恭, 柳澤 聖, 光冨 徹哉, 高橋 隆

    日本癌学会総会記事   64回   402 - 402   2005.9

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  • 肺癌におけるDicerの発現低下と外科切除後生存期間の短縮

    苅部 陽子, 田中 寿明, 長田 啓隆, 冨田 秀太, 立松 義朗, 柳澤 聖, 谷田部 恭, 高見澤 潤一, 三好 新一郎, 光冨 徹哉, 高橋 隆

    日本癌学会総会記事   64回   389 - 389   2005.9

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  • Reduced expression of Dicer associated with poor prognosis in lung cancer patients

    Y Karube, H Tanaka, H Osada, S Tomida, Y Tatematsu, K Yanagisawa, Y Yatabe, J Takamizawa, S Miyoshi, T Mitsudomi, T Takahashi

    CANCER SCIENCE   96 ( 2 )   111 - 115   2005.2

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    Emerging evidence suggests that microRNA, which are well-conserved, abundant and small regulatory RNA, may be involved in the pathogenesis of human cancers. We recently reported that expression of let-7 was frequently reduced in lung cancers, and that reduced let-7 expression was significantly associated with shorter patient survival. Two members of the double-stranded RNA-specific endonuclease family, Dicer and Drosha, convert precursor forms of microRNA into their mature forms using a stepwise process. In the present study, we examined expression levels of these genes in 67 non-small cell lung cancer cases, and found for the first time that Dicer expression levels were reduced in a fraction of lung cancers with a significant prognostic impact on the survival of surgically treated cases. It should be noted that multivariate COX regression analysis showed that the prognostic impact of Dicer (P = 0.001) appears to be independent of disease stage (P = 0.001), while logistic regression analysis demonstrated that the higher incidence of reduced Dicer expression in poorly differentiated tumors remained significant even after correction for other parameters (P = 0.02). Given the fundamental and multiple biological roles of Dicer in various cellular processes, our results suggest the involvement of reduced Dicer expression in the development of lung cancers, thus warranting further investigations of the underlying mechanisms, which can be expected to enhance understanding of the molecular pathogenesis of this fatal cancer.

    DOI: 10.1111/j.1349-7006.2005.00015.x

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  • Throwing new light on lung cancer pathogenesis: Updates on three recent topics

    S Tomida, Y Yatabe, K Yanagisawa, T Mitsudomi, T Takahashi

    CANCER SCIENCE   96 ( 2 )   63 - 68   2005.2

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    Language:English   Publishing type:Book review, literature introduction, etc.   Publisher:WILEY-BLACKWELL  

    Lung cancers have become the leading cause of cancer deaths in Japan, claiming more than 55 000 lives annually. Unfortunately, substantial improvement in terms of cure rates has not been achieved over the last two decades, although during the same period of time in-depth basic knowledge of the molecular mechanisms, which underlies carcinogenesis and progression of this deadly group of neoplasms, has accumulated at an amazing pace. it has consequently become evident that they have many shared but also distinct features, when comparisons are made not only with other common epithelial cancers of adults, such as colon cancer, but also within the various histologic types of lung cancers themselves. This review article provides an up-date on cutting-edge research into the following three different topics, from which important new insights have been obtained. The first concerns genetic instability, especially chromosome instability, and checkpoint failure in lung cancers. Second, we deal with EGFR mutations, which shows revealing specificities in various aspects. Finally, advances in the expression profiling analysis of both transcriptomes and proteomes of lung cancers are summarized.

    DOI: 10.1111/j.1349-7006.2005.00021.x

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  • Artificial neural network approach for selection of susceptible single nucleotide polymorphisms and construction of prediction model on childhood allergic asthma

    Y Tomita, S Tomida, Y Hasegawa, Y Suzuki, T Shirakawa, T Kobayashi, H Honda

    BMC BIOINFORMATICS   5 ( 120 )   2004.9

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    Background: Screening of various gene markers such as single nucleotide polymorphism ( SNP) and correlation between these markers and development of multifactorial disease have previously been studied. Here, we propose a susceptible marker-selectable artificial neural network ( ANN) for predicting development of allergic disease.
    Results: To predict development of childhood allergic asthma (CAA) and select susceptible SNPs, we used an ANN with a parameter decreasing method (PDM) to analyze 25 SNPs of 17 genes in 344 Japanese people, and select 10 susceptible SNPs of CAA. The accuracy of the ANN model with 10 SNPs was 97.7% for learning data and 74.4% for evaluation data. Important combinations were determined by effective combination value (ECV) defined in the present paper. Effective 2-SNP or 3-SNP combinations were found to be concentrated among the 10 selected SNPs.
    Conclusion: ANN can reliably select SNP combinations that are associated with CAA. Thus, the ANN can be used to characterize development of complex diseases caused by multiple factors. This is the first report of automatic selection of SNPs related to development of multifactorial disease from SNP data of more than 300 patients.

    DOI: 10.1186/1471-2105-5-120

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  • 遺伝子発現プロファイル解析に基づく肺がん患者の予後予測モデルの構築

    冨田 秀太, 越川 克己, 谷田部 恭, 原野 知子, 小倉 信彦, 光冨 徹哉, 染 真人, 柳澤 聖, 高橋 利忠, 長田 啓隆, 高橋 隆

    日本癌学会総会記事   63回   452 - 453   2004.9

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  • ヒト肺癌におけるマイクロRNA let-7の発現と各種臨床因子との相関の解析

    高見澤 潤一, 小西 裕之, 柳澤 聖, 冨田 秀太, 長田 啓隆, 遠藤 秀紀, 原野 知子, 谷田部 恭, 梛野 正人, 二村 雄次, 光冨 徹哉, 高橋 隆

    日本癌学会総会記事   63回   404 - 405   2004.9

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  • 高転移性ヒト肺癌細胞亜株(LNM35)における,遺伝子・蛋白の発現プロファイル解析による転移関連因子の探求

    柳澤 聖, 小西 裕之, 冨田 秀太, 谷田部 恭, 光冨 徹哉, 長田 啓隆, 高橋 隆

    日本癌学会総会記事   63回   452 - 452   2004.9

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  • Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival

    J Takamizawa, H Konishi, K Yanagisawa, S Tomida, H Osada, H Endoh, T Harano, Y Yatabe, M Nagino, Y Nimura, T Mitsudomi, T Takahashi

    CANCER RESEARCH   64 ( 11 )   3753 - 3756   2004.6

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    In this study, we report for the first time reduced expression of the let-7 microRNA in human lung cancers. Interestingly, 143 lung cancer cases that had undergone potentially curative resection could be classified into two major groups according to let-7 expression in unsupervised hierarchical analysis, showing significantly shorter survival after potentially curative resection in cases with reduced let-7 expression (P = 0.0003). Multivariate COX regression analysis showed this prognostic impact to be independent of disease stage (hazard ratio = 2.17; P = 0.009). In addition, overexpression of let-7 in A549 lung adenocarcinoma cell line inhibited lung cancer cell growth in vitro. This study represents the first report of reduced expression of let-7 and the potential clinical and biological effects of such a microRNA alteration.

    DOI: 10.1158/0008-5472.CAN-04-0637

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  • Prognostic model of pulmonary adenocarcinoma by expression profiling of eight genes as determined by quantitative real-time reverse transcriptase polymerase chain reaction

    H Endoh, S Tomida, Y Yatabe, H Konishi, H Osada, K Tajima, T Kuwano, T Takahashi, T Mitsudomi

    JOURNAL OF CLINICAL ONCOLOGY   22 ( 5 )   811 - 819   2004.3

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    Purpose Recently, several expression-profiling experiments have shown that adenocarcinoma can be classified into subgroups that also reflect patient survival. In this study, we examined the expression patterns of 44 genes selected by these studies to test whether their expression patterns were relevant to prognosis in our cohort as well, and to create a prognostic model applicable to clinical practice,
    Patients and Methods Expression levels were determined in 85 adenocarcinoma patients by quantitative reverse transcriptase polymerase chain reaction. Cluster analysis was performed, and a prognostic model was created by the proportional hazards model using a stepwise method.
    Results Hierarchical clustering divided the cases into three major groups, and group B, comprising 21 cases, had significantly poor survival (P = .0297). Next, we tried to identify a smaller number of genes of particular predictive value, and eight genes (PTK7, CIT, SCNN1A, PGES, ERO1L, ZWINT, and two ESTs) were selected. We then calculated a risk index that was defined as a linear combination of gene expression values weighted by their estimated regression coefficients. The risk index was a significant independent prognostic factor (P = .0021) by multivariate analysis. Furthermore, the robustness of this model was confirmed using an independent set of 21 patients (P = .0085).
    Conclusion By analyzing a reasonably small number of genes, patients with adenocarcinoma could be stratified according to their prognosis. The prognostic model could be applicable to future decisions concerning treatment.
    (C) 2004 by American Society of Clinical Oncology.

    DOI: 10.1200/JCO.2004.04.109

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  • cDNAマイクロアレイによって選択された44個の遺伝子の発現解析による肺腺癌患者の予後予測モデル

    遠藤 秀紀, 冨田 秀太, 谷田部 恭, 小西 裕之, 長田 啓隆, 田嶋 公平, 桑野 博行, 高橋 隆, 光冨 徹哉

    日本癌学会総会記事   62回   502 - 502   2003.8

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  • cDNAマイクロアレイによって選択された44個の遺伝子の発現解析による肺腺癌患者の予後予測モデル

    遠藤 秀紀, 谷田部 恭, 冨田 秀太, 桑野 博行, 高橋 隆, 光冨 徹哉

    日本外科学会雑誌   104 ( 0 )   2003.4

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  • Analysis of expression profile using fuzzy adaptive resonance theory

    S Tomida, T Hanai, H Honda, T Kobayashi

    BIOINFORMATICS   18 ( 8 )   1073 - 1083   2002.8

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    Motivation: It is well understood that the successful clustering of expression profiles give beneficial ideas to understand the functions of uncharacterized genes. In order to realize such a successful clustering, we investigate a clustering method based on adaptive resonance theory (ART) in this report.
    Results: We apply Fuzzy ART as a clustering method for analyzing the time series expression data during sporulation of Saccharomyces cerevisiae. The clustering result by Fuzzy ART was compared with those by other clustering methods such as hierarchical clustering, k-means algorithm and self-organizing maps (SOMs). In terms of the mathematical validations, Fuzzy ART achieved the most reasonable clustering. We also verified the robustness of Fuzzy ART using noised data. Furthermore, we defined the correctness ratio of clustering, which is based on genes whose temporal expressions are characterized biologically. Using this definition, it was proved that the clustering ability of Fuzzy ART was superior to other clustering methods such as hierarchical clustering, k-means algorithm and SOMs. Finally, we validate the clustering results by Fuzzy ART in terms of biological functions and evidence.

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  • Construction of COD simulation model for activated sludge process by recursive fuzzy neural network

    S Tomida, T Hanai, H Honda, T Kobayashi

    JOURNAL OF CHEMICAL ENGINEERING OF JAPAN   34 ( 3 )   369 - 375   2001.3

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    Using a fuzzy neural network (FNN), we constructed a simulation model which estimates the effluent chemical oxygen demand (COD) value from daily routine measurements. Since the water quality of wastewater is changing day by day, an FNN model with a recursively renewing method of learning data (R-FNN) is proposed. With this R-FNN, Learning data used to construct an FNN model are renewed with elapsed time so as to estimate the effluent COD value with good accuracy. The estimation results for 9 weeks data using R-FNN were compared with those using a conventional FNN. The average error using the R-FNN model was 0.36 mg/l, while that using the conventional FNN was 1.50 mg/l. Moreover, estimation of the effluent COD throughout one year was carried out, and the average error was only 0.40 mg/l. This result can show the usefulness of the R-FNN for the simulation model of the activated sludge process.

    DOI: 10.1252/jcej.34.369

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  • Construction of COD simulation model for activated sludge process by fuzzy neural network

    S Tomida, T Hanai, N Ueda, H Honda, T Kobayashi

    JOURNAL OF BIOSCIENCE AND BIOENGINEERING   88 ( 2 )   215 - 220   1999.8

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    Fuzzy neural network (FNN) was applied to construct a simulation model for estimating the effluent chemical oxygen demand (COD) value of an activated sludge process in a "U" plant, in which most of process variables were measured once an hour. The constructed FNN model could simulate periodic changes in COD with high accuracy. Comparing the simulation result obtained using the FNN model with that obtained using the multiple regression analysis (MRA) model, it was found that the FNN model had 3.7 times higher accuracy than the MRA model. The FNN models corresponding to each of the four seasons were also constructed. Analyzing the fuzzy rules acquired from the FNN models after learning, the operational characteristic of this plant could be elucidated. Construction of the simulation model for another plant "A", in which process variables were measured once a day, was also carried out. This FNN model also had a relatively high accuracy.

    DOI: 10.1016/S1389-1723(99)80205-9

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Industrial property rights

  • Fast diagnosis and personalized treatments for acne

    TOMIDA Shuta

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    Application no:US201261612290P  Date applied:2012.3.17

    Announcement no:WO2013142378A9  Date announced:2014.1.23

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  • 細胞増殖阻害剤

    高橋 隆, 山口 知也, 冨田 秀太

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    Applicant:国立大学法人名古屋大学

    Application no:JP2009062975  Date applied:2009.7.17

    Announcement no:WO2010-008069  Date announced:2010.1.21

    J-GLOBAL

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  • 肺腺癌患者の術後再発を予測するための方法及び組成物

    高橋 隆, 冨田 秀太, 竹内 俊幸, 谷田部 恭, 光冨 徹哉

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    Applicant:国立大学法人名古屋大学, 株式会社Oncomics, 愛知県

    Application no:JP2008073982  Date applied:2008.12.26

    Announcement no:WO2009-084740  Date announced:2009.7.9

    J-GLOBAL

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  • 質量分析法を利用した複数癌腫の血液検出のための方法および生物マーカー

    高橋 隆, 柳澤 聖, 冨田 秀太, 竹内 俊幸, 久寿米木, 松尾 恵太郎, 田島 和雄

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    Applicant:国立大学法人名古屋大学, 株式会社Oncomics, 愛知県

    Application no:特願2008-235216  Date applied:2008.9.12

    Announcement no:特開2010-066225  Date announced:2010.3.25

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  • 肺腺癌細胞に対する薬剤の有効性評価法

    高橋 隆, 柳澤 聖, 冨田 秀太

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    Applicant:国立大学法人名古屋大学

    Application no:特願2007-110320  Date applied:2007.4.19

    Announcement no:特開2008-263837  Date announced:2008.11.6

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  • 肺癌患者の術後予後予測のための生物マーカー及びその方法

    高橋 隆, 柳澤 聖, 冨田 秀太, 谷田部 恭, 光冨 徹哉

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    Applicant:国立大学法人名古屋大学, 愛知県

    Application no:特願2006-092568  Date applied:2006.3.29

    Announcement no:特開2007-263896  Date announced:2007.10.11

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  • 癌患者の術後の予後又は転移可能性を予測するための組成物及び方法

    高橋 隆, 冨田 秀太, 柳澤 聖

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    Applicant:国立大学法人名古屋大学

    Application no:特願2005-379867  Date applied:2005.12.28

    Announcement no:特開2007-175023  Date announced:2007.7.12

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  • 肺腺癌患者の術後予後を予測するための方法及び組成物

    高橋 隆, 冨田 秀太, 谷田部 恭, 光冨 徹哉, 竹内 俊幸

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    Applicant:国立大学法人名古屋大学, 愛知県, 社団法人バイオ産業情報化コンソーシアム

    Application no:特願2005-291588  Date applied:2005.10.4

    Announcement no:特開2007-097486  Date announced:2007.4.19

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  • 肺癌組織中の遺伝子発現強度を識別する方法

    高橋 隆, 冨田 秀太, 光冨 徹哉, 谷田部 恭, 小倉 信彦, 染 真人

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    Applicant:愛知県, 富士フイルム株式会社

    Application no:特願2003-415119  Date applied:2003.12.12

    Announcement no:特開2005-261201  Date announced:2005.9.29

    Patent/Registration no:特許第5192632号  Date issued:2013.2.8

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  • 遺伝子のクラスタリング方法

    小林 猛, 本多 裕之, 花井 泰三, 冨田 秀太

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    Applicant:財団法人名古屋産業科学研究所

    Application no:特願2000-373765  Date applied:2000.12.8

    Announcement no:特開2002-175306  Date announced:2002.6.21

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Awards

  • Incitement Award of the Japanese Cancer Association

    2010   Japanese Cancer Association  

    TOMIDA Shuta

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Research Projects

  • Development of next-generation precision medicine targeting the pathways on which driver gene mutation-positive lung cancer depends

    Grant number:20H03771  2020.04 - 2023.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)  Grant-in-Aid for Scientific Research (B)

    冨田 秀太, 豊岡 伸一, 大橋 圭明, 山本 寛斉, 諏澤 憲

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    Grant amount:\17810000 ( Direct expense: \13700000 、 Indirect expense:\4110000 )

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  • 分子バーコードを用いた高感度遺伝子変異解析と機能解析

    2017.04 - 2020.03

    日本学術振興会  科学研究費補助金(基盤研究(C)) 

    冨田 秀太

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    Authorship:Principal investigator  Grant type:Competitive

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  • Cクラス・Mクラスシグネチャーを統合したECM分類によるがん分子病態の解明

    2016.04 - 2018.03

    文部科学省  科学研究費補助金(新学術領域研究(研究領域提案型)) 

    冨田 秀太

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    Authorship:Principal investigator  Grant type:Competitive

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  • 次世代シーケンサーを用いたスキンマイクロバイオームの解析と新規治療法の開発

    Grant number:26860902  2014 - 2015

    文部科学省  科学研究費補助金(若手研究(B))  若手研究(B)

    冨田 秀太

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3770000 ( Direct expense: \2900000 、 Indirect expense:\870000 )

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  • Gene set-based identification of oncogenic pathways related to relapse-related death in lung adenocarcinomas

    Grant number:19790969  2007 - 2008

    Ministry of Education, Culture, Sports, Science and Technology  Grants-in-Aid for Scientific Research(若手研究(B))  若手研究(B)

    Shuta TOMIDA

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    Authorship:Principal investigator  Grant type:Competitive

    Grant amount:\3000000 ( Direct expense: \2700000 、 Indirect expense:\300000 )

    研究代表者らは、"機能的に関連した一連の遺伝子セット"を解析単位とする解析手法を用いる事によって、肺腺癌の多様性に関する"ターゲットパスウェイ"の抽出に成功した。この"ターゲットパスウェイ"を基にした判別モデルを用いて、独立した肺腺癌データを解析したところ、統計的に有意に、術後予後良好群と予後不良群に分類することができた。また、肺腺癌細胞株を用いた検討により、"ターゲットパスウェイ"に対する阻害活性を持つ薬剤の感受性予測モデルの構築にも成功した。

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Class subject in charge

  • Introduction to Medical Genomics (2022academic year) 1st semester  - 火1~2

  • Biomedical data science (2022academic year) Fourth semester  - 月4~6

  • Introduction to Clinical Medicine and Dentistry (2022academic year) Concentration  - その他

  • Biomedical data science (2021academic year) Fourth semester  - 月4~6

  • Introduction to Clinical Medicine and Dentistry (2021academic year) Concentration  - その他

  • Biomedical data science (2020academic year) Fourth semester  - その他

  • Introduction to Clinical Medicine and Dentistry (2020academic year) Concentration  - その他

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