2021/12/10 更新

写真a

トモノブ ナホコ
友信 奈保子
TOMONOBU Nahoko
所属
医歯薬学域 助教(特任)
職名
助教(特任)
外部リンク

学位

  • 博士(医学) ( 2021年3月   岡山大学 )

  • 博士(医学) ( 岡山大学 )

研究キーワード

  • 細胞生物学

  • S100タンパク質

  • がん

研究分野

  • ライフサイエンス / 医化学

学歴

  • 岡山大学    

    2017年4月 - 2021年3月

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  • 岡山大学    

    2015年4月 - 2017年3月

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  • 大阪工業大学   Faculty of Engineering  

    2011年4月 - 2015年3月

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経歴

  • 岡山大学学術研究院   医歯薬学域 細胞生物学   特任助教

    2021年4月

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  • 岡山大学   ナノバイオ標的医療イノベーションセンター   特別契約技術職員

    2017年4月 - 2021年3月

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所属学協会

 

論文

  • REIC/Dkk-3 Gene Therapy Induces Immunogenic Cell Death in a Mouse Model of Malignant Mesothelioma. 国際誌

    Kenji Araki, Naoya Yamamuro, Nahoko Tomonobu, Hiromi Kumon

    Anticancer research   41 ( 10 )   4837 - 4855   2021年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND/AIM: The adenovirus vector- carrying reduced expression in immortalized cell (REIC) gene (Ad-REIC) increases endoplasmic reticulum stress chaperone GRP78/BiP expression and induces the JNK-mediated apoptotic pathway. We aimed to determine whether Ad-REIC-induced apoptotic cell death can trigger immunogenic cell death (ICD). MATERIALS AND METHODS: We examined the emission of damage-associated molecular patterns in vitro and the vaccination effect in vivo. We determined the immunological changes in the tumour microenvironment by putative ICD inducers and the combined effects of immune checkpoint blockade therapies. RESULTS: Ad-REIC induced the release of high-mobility group box 1 and adenosine triphosphate and the translocation of calreticulin in murine mesothelioma AB12 cells. The vaccination effect was elicited by Ad-REIC treatment in vivo. The effect of Ad-REIC was potentiated by anti-cytotoxic T-lymphocyte-associated protein 4 antibody treatment in a murine mesothelioma AB1-HA cell model. CONCLUSION: Ad-REIC induces ICD in malignant mesothelioma.

    DOI: 10.21873/anticanres.15298

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  • RUNX2 Phosphorylation by Tyrosine Kinase ABL Promotes Breast Cancer Invasion (vol 11, 665273, 2021)

    Fang He, Yoshinori Matsumoto, Yosuke Asano, Yuriko Yamamura, Takayuki Katsuyama, Jose La Rose, Nahoko Tomonobu, Ni Luh Gede Yoni Komalasari, Masakiyo Sakaguchi, Robert Rottapel, Jun Wada

    FRONTIERS IN ONCOLOGY   11   2021年7月

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    記述言語:英語   出版者・発行元:FRONTIERS MEDIA SA  

    DOI: 10.3389/fonc.2021.729192

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

    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-JMM   99 ( 1 )   131 - 145   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER HEIDELBERG  

    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.

    DOI: 10.1007/s00109-020-02001-x

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  • Dysfunction of CD8+PD-1+T cells in type 2 diabetes caused by the impairment of metabolism-immune axis

    Ichiro Nojima, Shingo Eikawa, Nahoko Tomonobu, Yoshiko Hada, Nobuo Kajitani, Sanae Teshigawara, Satoshi Miyamoto, Atsuhito Tone, Haruhito A. Uchida, Atsuko Nakatsuka, Jun Eguchi, Kenichi Shikata, Heiichiro Udono, Jun Wada

    SCIENTIFIC REPORTS   10 ( 1 )   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE RESEARCH  

    The metabolic changes and dysfunction in CD8+T cells may be involved in tumor progression and susceptibility to virus infection in type 2 diabetes (T2D). In C57BL/6JJcl mice fed with high fat-high sucrose chow (HFS), multifunctionality of CD8+splenic and tumor-infiltrating lymphocytes (TILs) was impaired and associated with enhanced tumor growth, which were inhibited by metformin. In CD8+splenic T cells from the HFS mice, glycolysis/basal respiration ratio was significantly reduced and reversed by metformin. In the patients with T2D (DM), multifunctionality of circulating CD8+PD-1+T cells stimulated with PMA/ionomycin as well as with HLA-A*24:02 CMV peptide was dampened, while metformin recovered multifunctionality. Both glycolysis and basal respiration were reduced in DM, and glycolysis was increased by metformin. The disturbance of the link between metabolism and immune function in CD8+PD-1+T cells in T2D was proved by recovery of antigen-specific and non-specific cytokine production via metformin-mediated increase in glycolytic activity.

    DOI: 10.1038/s41598-020-71946-3

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  • Neuroplastin beta-mediated upregulation of solute carrier family 22 member 18 antisense (SLC22A18AS) plays a crucial role in the epithelial-mesenchymal transition, leading to lung cancer cells' enhanced motility

    Karolina Bajkowska, I. Wayan Sumardika, Nahoko Tomonobu, Youyi Chen, Ken-ichi Yamamoto, Rie Kinoshita, Hitoshi Murata, Ni Luh Gede Yoni Komalasari, Fan Jiang, Akira Yamauchi, I. Made Winarsa Ruma, Carlos Ichiro Kasano-Camones, Yusuke Inoue, Masakiyo Sakaguchi

    BIOCHEMISTRY AND BIOPHYSICS REPORTS   22   2020年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER  

    Our recent study revealed an important role of the neuroplastin (NPTN)beta downstream signal in lung cancer dissemination in the lung. The molecular mechanism of the signal pathway downstream of NPTN beta is a serial activation of the key molecules we identified: tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) adaptor, nuclear factor (NF)IA/NFIB heterodimer transcription factor, and SAM pointed-domain containing ETS transcription factor (SPDEF). The question of how dissemination is controlled by SPDEF under the activated NPTN beta has not been answered. Here, we show that the NPTN beta-SPDEF-mediated induction of solute carrier family 22 member 18 antisense (SLC22A18AS) is definitely required for the epithelial-mesenchymal transition (EMT) through the NPTN beta pathway in lung cancer cells. In vitro, the induced EMT is linked to the acquisition of active cellular motility but not growth, and this is correlated with highly disseminative tumor progression in vivo. The publicly available data also show the poor survival of SLC22A18AS-overexpressing lung cancer patients. Taken together, these data highlight a crucial role of SLC22A18AS in lung cancer dissemination, which provides novel input of this molecule to the signal cascade of NPTN beta. Our findings contribute to a better understanding of NPTN beta-mediated lung cancer metastasis.

    DOI: 10.1016/j.bbrep.2020.100768

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  • exMCAM-Fc, an S100A8/A9-mediated-metastasis blocker, efficiently reduced the number of circulating tumor cells that appeared in the blood flow

    Nahoko Tomonobu, Rie Kinoshita, Masakiyo Sakaguchi

    MOLECULAR BIOLOGY REPORTS   47 ( 6 )   4879 - 4883   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Metastasis is the major cause of treatment failure in cancer patients and of cancer-associated death so that therapeutic regulation of metastasis is very important subject for the cancer treatment. We have been reported that S100A8/A9, a heterodimer complex of S100A8 and S100A9, and its receptors play a crucial role in the lung tropic cancer metastasis, i.e., S100A8/A9 is actively secreted from the lung when cancer mass exists even at remote area from the lung and then functions to attract the distant cancer cells to the lung since cancer cells own the S100A8/A9 receptor(s) on their cell surface. Interestingly, one of the newly developed decoys, exMCAM-Fc, a Fc fusion protein with the extracellular region of melanoma cell adhesion molecule (MCAM), one of the S100A8/A9 receptors, that could prevent the interaction of S100A8/A9 with MCAM, efficiently suppressed the lung tropic cancer metastasis through exerting the several inhibitory effects on the S100A8/A9-mediated cancer cell events including enhanced mobility, invasion and attachment to the endothelial cells. However, it still remains to clarify if the decoy will reduce the number of circulating tumor cells (CTCs) that are defined as substantial cells in the context of organ tropic cancer metastasis. Here, we first show that exMCAM-Fc effectively reduces the number of CTCs in the blood flow of the melanoma bearing mice. The novel finding reinforces the suppressive role of exMCAM-Fc on the cancer metastasis. We therefore expect that exMCAM-Fc may greatly contribute to reduce treatment failure by the efficient blocking of the life threatening cancer metastasis.

    DOI: 10.1007/s11033-020-05495-3

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  • Xylitol acts as an anticancer monosaccharide to induce selective cancer death via regulation of the glutathione level

    Nahoko Tomonobu, Ni Luh Gede Yoni Komalasari, I. Wayan Sumardika, Fan Jiang, Youyi Chen, Ken-ichi Yamamoto, Rie Kinoshita, Hitoshi Murata, Yusuke Inoue, Masakiyo Sakaguchi

    CHEMICO-BIOLOGICAL INTERACTIONS   324   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Herbal medicines and their bioactive compounds are increasingly being recognized as useful drugs for cancer treatments. The parasitic fungus Cordyceps militaris is an attractive anticancer herbal since it shows very powerful anticancer activity due to its phytocompound cordycepin. We previously discovered and reported that a high amount of xylitol is present in Cordyceps militaris extract, and that xylitol unexpectedly showed anticancer activity in a cancer-selective manner. We thus hypothesized that xylitol could become a useful supplement to help prevent various cancers, if we can clarify the specific machinery by which xylitol induces cancer cell death. It is also unclear whether xylitol acts on cancer suppression in vivo as well as in vitro. Here we show for the first time that induction of the glutathione-degrading enzyme CHAC1 is the main cause of xylitol-induced apoptotic cell death in cancer cells. The induction of CHAC1 is required for the endoplasmic reticulum (ER) stress that is triggered by xylitol in cancer cells, and is linked to a second induction of oxidative stress in the treated cells, and eventually leads to apoptotic cell death. Our in vivo approach also demonstrated that an intravenous injection of xylitol had a tumor-suppressing effect in mice, to which the xylitol-triggered ER stress also greatly contributed. We also observed that xylitol efficiently sensitized cancer cells to chemotherapeutic drugs. Based on our findings, a chemotherapeutic strategy combined with xylitol might improve the outcomes of patients facing cancer.

    DOI: 10.1016/j.cbi.2020.109085

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  • S100 Soil Sensor Receptors and Molecular Targeting Therapy Against Them in Cancer Metastasis

    Nahoko Tomonobu, Rie Kinoshita, Masakiyo Sakaguchi

    TRANSLATIONAL ONCOLOGY   13 ( 4 )   2020年4月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE INC  

    The molecular mechanisms underlying the 'seed and soil' theory are unknown. S100A8/A9 (a heterodimer complex of S100A8 and S100A9 proteins that exhibits a 'soil signal') is a ligand for Toll-like receptor 4, causing distant melanoma cells to approach the lung as a 'seeding' site. Unknown soil sensors for S100A8/A9 may exist, e.g., extracellular matrix metalloproteinase inducer, neuroplastin, activated leukocyte cell adhesion molecule, and melanoma cell adhesion molecule. We call these receptor proteins 'novel S100 soil sensor receptors (novel SSSRs).' Here we review and summarize a crucial role of the S100A8/A9-novel SSSRs' axis in cancer metastasis. The binding of S100A8/A9 to individual SSSRs is important in cancer metastasis via upregulations of the epithelial-mesenchymal transition, cellular motility, and cancer cell invasiveness, plus the formation of an inflammatory immune suppressive environment in metastatic organ(s). These metastatic cellular events are caused by the SSSR-featured signal transductions we identified that provide cancer cells a driving force for metastasis. To deprive cancer cells of these metastatic forces, we developed novel biologics that prevent the interaction of S100A8/A9 with SSSRs, followed by the efficient suppression of S100A8/A9mediated lung-tropic metastasis in vivo.

    DOI: 10.1016/j.tranon.2020.100753

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  • Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness

    Youyi Chen, I. Wayan Sumardika, Nahoko Tomonobu, Rie Kinoshita, Yusuke Inoue, Hidekazu Iioka, Yosuke Mitsui, Ken Saito, I. Made Winarsa Ruma, Hiroki Sato, Akira Yamauchi, Hitoshi Murata, Ken-ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Junichiro Futami, Miyoko Kubo, Endy Widya Putranto, Takashi Murakami, Ming Liu, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    NEOPLASIA   21 ( 7 )   627 - 640   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE INC  

    Metastatic breast cancer is the leading cause of cancer-associated death in women. The progression of this fatal disease is associated with inflammatory responses that promote cancer cell growth and dissemination, eventually leading to a reduction of overall survival. However, the mechanism(s) of the inflammation-boosted cancer progression remains unclear. In this study, we found for the first time that an extracellular cytokine, S100A8/A9, accelerates breast cancer growth and metastasis upon binding to a cell surface receptor, melanoma cell adhesion molecule (MCAM). Our molecular analyses revealed an important role of ETS translocation variant 4 (ETV4), which is significantly activated in the region downstream of MCAM upon S100A8/A9 stimulation, in breast cancer progression in vitro as well as in vivo. The MCAM-mediated activation of ETV4 induced a mobile phenotype called epithelial-mesenchymal transition (EMT) in cells, since we found that ETV4 transcriptionally upregulates ZEB1, a strong EMT inducer, at a very high level. In contrast, downregulation of either MCAM or ETV4 repressed EMT, resulting in greatly weakened tumor growth and lung metastasis. Overall, our results revealed that ETV4 is a novel transcription factor regulated by the S100A8/A9-MCAM axis, which leads to EMT through ZEB1 and thereby to metastasis in breast cancer cells. Thus, therapeutic strategies based on our findings might improve patient outcomes.

    DOI: 10.1016/j.neo.2019.04.006

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  • Newly developed anti-S100A8/A9 monoclonal antibody efficiently prevents lung tropic cancer metastasis

    Rie Kinoshita, Hiroki Sato, Akira Yamauchi, Yuta Takahashi, Yusuke Inoue, I. Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Kota Araki, Kazuhiko Shien, Shuta Tomida, Hidejiro Torigoe, Kei Namba, Eisuke Kurihara, Yusuke Ogoshi, Hitoshi Murata, Ken-ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I. Made Winarsa Ruma, Hiromasa Yamamoto, Junichi Soh, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    INTERNATIONAL JOURNAL OF CANCER   145 ( 2 )   569 - 575   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    The metastatic dissemination of cancer cells to remote areas of the body is the most problematic aspect in cancer patients. Among cancers, melanomas are notoriously difficult to treat due to their significantly high metastatic potential even during early stages. Hence, the establishment of advanced therapeutic approaches to regulate metastasis is required to overcome the melanoma disease. An accumulating mass of evidence has indicated a critical role of extracellular S100A8/A9 in melanoma distant metastasis. Lung S100A8/A9 is induced by melanoma cells from distant organs and it attracts these cells to its enriched lung environment since melanoma cells possess several receptors that sense the S100A8/A9 ligand. We hence aimed to develop a neutralizing antibody against S100A8/A9 that would efficiently block melanoma lung metastasis. Our protocol provided us with one prominent antibody, Ab45 that efficiently suppressed not only S100A8/A9-mediated melanoma mobility but also lung tropic melanoma metastasis in a mouse model. This prompted us to make chimeric Ab45, a chimera antibody consisting of mouse Ab45-Fab and human IgG2-Fc. Chimeric Ab45 also showed significant inhibition of the lung metastasis of melanoma. From these results, we have high hopes that the newly produced antibody will become a potential biological tool to block melanoma metastasis in future clinical settings.

    DOI: 10.1002/ijc.31982

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  • Convenient methodology for extraction and subsequent selective propagation of mouse melanocytes in culture from adult mouse skin tissue

    Nahoko Tomonobu, Rie Kinoshita, I. Wayan Sumardika, Youyi Chen, Yusuke Inoue, Akira Yamauchi, Ken-ichi Yamamoto, Hitoshi Murata, Masakiyo Sakaguchi

    BIOCHEMISTRY AND BIOPHYSICS REPORTS   18   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER  

    Mouse melanoma B16-BL6 cells are useful cells for cancer metastatic studies. To understand the metastatic principle at molecular levels, it is necessary to carry out experiments in which cancer cells and their normal counterparts are compared. However, unlike normal human melanocytes, preparation of normal mouse melanocytes is quite difficult due to the lack of marketing and insufficient information on an established protocol for primary culture of mouse melanocytes. In this study, we aimed to establish a convenient method for primary culture of mouse melanocytes on the basis of the protocol for human melanocytes. The main obstacles to preparing pure mouse melanocytes are how to digest mouse skin tissue and how to reduce the contamination of keratinocytes and fibroblasts. The obstacles were overcome by collagenase digestion for skin specimens, short time trypsinization for separating melanocytes and keratinocytes, and use of 12-O-Tetradecanoylphorbol 13-acetate (TPA) and cholera toxin in the culture medium. These supplements act to prevent the proliferation of keratinocytes and fibroblasts, respectively. The convenient procedure enabled us to prepare a pure culture of normal mouse melanocytes. Using enriched normal mouse melanocytes and cancerous B16-BL6 cells, we compared the expression levels of melanoma cell adhesion molecule (MCAM), an important membrane protein for melanoma metastasis, in the cells. The results showed markedly higher expression of MCAM in B16-BL6 cells than in normal mouse melanocytes.

    DOI: 10.1016/j.bbrep.2019.100619

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  • exSSSRs (extracellular S100 soil sensor receptors)-Fc fusion proteins work as prominent decoys to S100A8/A9-induced lung tropic cancer metastasis

    Rie Kinoshita, Hiroki Sato, Akira Yamauchi, Yuta Takahashi, Yusuke Inoue, I. Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Kota Araki, Kazuhiko Shien, Shuta Tomida, Hidejiro Torigoe, Kei Namba, Eisuke Kurihara, Yusuke Ogoshi, Hitoshi Murata, Ken-ichi Yamamoto, Junichiro Futami, Endy Widya Putranto, I. Made Winarsa Ruma, Hiromasa Yamamoto, Junichi Soh, Toshihiko Hibino, Masahiro Nishibori, Eisaku Kondo, Shinichi Toyooka, Masakiyo Sakaguchi

    INTERNATIONAL JOURNAL OF CANCER   144 ( 12 )   3138 - 3145   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Within the "seed and soil" theory of organ tropic cancer metastasis is a growing compilation of evidence that S100A8/A9 functions as a soil signal that attracts cancer cells to certain organs, which prove beneficial to their growth. S100A8/A9-sensing receptors including Toll-like receptor 4 (TLR4), advanced glycation end products (RAGE), and also important receptors we recently succeeded in identifying (EMMPRIN, NPTN beta, MCAM, and ALCAM) have the potential to become promising therapeutic targets. In our study, we prepared extracellular regions of these novel molecules and fused them to human IgG2-Fc to extend half-life expectancy, and we evaluated the anti-metastatic effects of the purified decoy proteins on metastatic cancer cells. The purified proteins markedly suppressed S100A8/A9-mediated lung tropic cancer metastasis. We hence expect that our novel biologics may become a prominent medicine to prevent cancer metastasis in clinical settings through cutting the linkage between "seed and soil".

    DOI: 10.1002/ijc.31945

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  • Neuroplastin- mediates S100A8/A9-induced lung cancer disseminative progression

    I. Wayan Sumardika, Youyi Chen, Nahoko Tomonobu, Rie Kinoshita, I. Made Winarsa Ruma, Hiroki Sato, Eisaku Kondo, Yusuke Inoue, Akira Yamauchi, Hitoshi Murata, Ken-ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Junichiro Futami, Endy Widya Putranto, Toshihiko Hibino, Masahiro Nishibori, Shinichi Toyooka, Masakiyo Sakaguchi

    MOLECULAR CARCINOGENESIS   58 ( 6 )   980 - 995   2019年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Compiling evidence indicates an unusual role of extracellular S100A8/A9 in cancer metastasis. S100A8/A9 secreted from either cancer cells or normal cells including epithelial and inflammatory cells stimulates cancer cells through S100A8/A9 sensor receptors in an autocrine or paracrine manner, leading to cancer cell metastatic progression. We previously reported a novel S100A8/A9 receptor, neuroplastin- (NPTN), which plays a critical role in atopic dermatitis when it is highly activated in keratinocytes by an excess amount of extracellular S100A8/A9 in the inflammatory skin lesion. Interestingly, our expression profiling of NPTN showed significantly high expression levels in lung cancer cell lines in a consistent manner. We hence aimed to determine the significance of NPTN as an S100A8/A9 receptor in lung cancer. Our results showed that NPTN has strong ability to induce cancer-related cellular events, including anchorage-independent growth, motility and invasiveness, in lung cancer cells in response to extracellular S100A8/A9, eventually leading to the expression of a cancer disseminative phenotype in lung tissue in vivo. Mechanistic investigation revealed that binding of S100A8/A9 to NPTN mediates activation of NFIA and NFIB and following SPDEF transcription factors through orchestrated upstream signals from TRAF2 and RAS, which is linked to anchorage-independent growth, motility and invasiveness. Overall, our results indicate the importance of the S100A8/A9-NPTN axis in lung cancer disseminative progression and reveal a pivotal role of its newly identified downstream signaling, TRAF2/RAS-NFIA/NFIB-SPDEF, in linking to the aggressive development of lung cancers.

    DOI: 10.1002/mc.22987

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  • Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts

    Yosuke Mitsui, Nahoko Tomonobu, Masami Watanabe, Rie Kinoshita, I. Wayan Sumardika, Chen Youyi, Hitoshi Murata, Ken-ichi Yamamoto, Takuya Sadahira, Acosta Gonzalez Herik Rodrigo, Hitoshi Takamatsu, Kota Araki, Akira Yamauchi, Masahiro Yamamura, Hideyo Fujiwara, Yusuke Inoue, Junichiro Futami, Ken Saito, Hidekazu Iioka, Eisaku Kondo, Masahiro Nishibori, Shinichi Toyooka, Yasuhiko Yamamoto, Yasutomo Nasu, Masakiyo Sakaguchi

    ONCOLOGY RESEARCH   27 ( 8 )   945 - 956   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:COGNIZANT COMMUNICATION CORP  

    S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11-RAGE-TPL2-COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

    DOI: 10.3727/096504019X15555408784978

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  • Melanoma cell adhesion molecule is the driving force behind the dissemination of melanoma upon S100A8/A9 binding in the original skin lesion

    Youyi Chen, I. Wayan Sumardika, Nahoko Tomonobu, I. Made Winarsa Ruma, Rie Kinoshita, Eisaku Kondo, Yusuke Inoue, Hiroki Sato, Akira Yamauchi, Hitoshi Murata, Ken-ichi Yamamoto, Shuta Tomida, Kazuhiko Shien, Hiromasa Yamamoto, Junichi Soh, Ming Liu, Junichiro Futami, Kaori Sasai, Hiroshi Katayama, Miyoko Kubo, Endy Widya Putranto, Toshihiko Hibino, Bei Sun, Masahiro Nishibori, Shinichi Toyooka, Masakiyo Sakaguchi

    CANCER LETTERS   452   178 - 190   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER IRELAND LTD  

    Since metastasis accounts for the majority of cancer-associated deaths, studies on the mechanisms of metastasis are needed to establish innovative strategies for cancer treatment. We previously reported that melanoma cell adhesion molecule (MCAM) functions as a critical receptor for S100A8/A9, and binding of S100A8/A9 to MCAM results in the migration of melanoma cells to lung tissue. However, the critical role of MCAM in the original melanoma skin lesion is still not clear. In this study, we aimed to determine the importance of the S100A8/A9-MCAM axis in melanoma dissemination in a skin lesion as a critical early step for metastasis. Mechanistic studies revealed the downstream signaling of MCAM that signaled the induction of metastasis. S100A8/A9-MCAM binding activates mitogen-activated protein kinase kinase kinase 8 (MAP3K8), also termed TPL2, leading to strong activation of the transcription factor ETV4 and subsequent induction of matrix metalloproteinase-25 (MMP25), and finally to induction of melanoma lung tropic metastasis. Collectively, our results demonstrate a crucial role of the S100A8/A9-MCAM signaling axis in metastatic onset of melanoma cells and indicate that strategies targeting the identified pathway may be useful for the establishment of innovative anti-cancer therapies.

    DOI: 10.1016/j.canlet.2019.03.023

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  • Extracellular S100A11 Plays a Critical Role in Spread of the Fibroblast Population in Pancreatic Cancers

    Hitoshi Takamatsu, Ken-ichi Yamamoto, Nahoko Tomonobu, Hitoshi Murata, Yusuke Inoue, Akira Yamauchi, I. Wayan Sumardika, Youyi Chen, Rie Kinoshita, Masahiro Yamamura, Hideyo Fujiwara, Yosuke Mitsui, Kota Araki, Junichiro Futami, Ken Saito, Hidekazu Iioka, I. Made Winarsa Ruma, Endy Widya Putranto, Masahiro Nishibori, Eisaku Kondo, Yasuhiko Yamamoto, Shinichi Toyooka, Masakiyo Sakaguchi

    ONCOLOGY RESEARCH   27 ( 6 )   713 - 727   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:COGNIZANT COMMUNICATION CORP  

    The fertile stroma in pancreatic ductal adenocarcinomas (PDACs) has been suspected to greatly contribute to PDAC progression. Since the main cell constituents of the stroma are fibroblasts, there is crosstalking(s) between PDAC cells and surrounding fibroblasts in the stroma, which induces a fibroblast proliferation burst. We have reported that several malignant cancer cells including PDAC cells secrete a pronounced level of S100A11, which in turn stimulates proliferation of cancer cells via the receptor for advanced glycation end products (RAGE) in an autocrine manner. Owing to the RAGE(+) expression in fibroblasts, the extracellular abundant S100A11 will affect adjacent fibroblasts. In this study, we investigated the significance of the paracrine axis of S100A11-RAGE in fibroblasts for their proliferation activity. In in vitro settings, extracellular S100A11 induced upregulation of fibroblast proliferation. Our mechanistic studies revealed that the induction is through RAGE-MyD88-mTOR-p70 S6 kinase upon S100A11 stimulation. The paracrine effect on fibroblasts is linked mainly to triggering growth but not cellular motility. Thus, the identified pathway might become a potential therapeutic target to suppress PDAC progression through preventing PDAC-associated fibroblast proliferation.

    DOI: 10.3727/096504018X15433161908259

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  • Embigin Promotes Prostate Cancer Progression by S100A4-Dependent and-Independent Mechanisms

    I. Made Winarsa Ruma, Rie Kinoshita, Nahoko Tomonobu, Yusuke Inoue, Eisaku Kondo, Akira Yamauchi, Hiroki Sato, I. Wayan Sumardika, Youyi Chen, Ken-Ichi Yamamoto, Hitoshi Murata, Shinichi Toyooka, Masahiro Nishibori, Masakiyo Sakaguchi

    CANCERS   10 ( 7 )   2018年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI  

    Embigin, a transmembrane glycoprotein belonging to the immunoglobulin superfamily, is involved in prostate and mammary gland development. As embigin's roles in cancer remain elusive, we studied its biological functions and interaction with extracellular S100A4 in prostate cancer progression. We found by a pull-down assay that embigin is a novel receptor for S100A4, which is one of the vital cancer microenvironment milleu. Binding of extracellular S100A4 to embigin mediates prostate cancer progression by inhibition of AMPK activity, activation of NF-kappa B, MMP9 and mTORC1 signaling, and inhibition of autophagy, which increase prostate cancer cell motility. We also found that embigin promotes prostate cancer growth, spheroid-and colony-forming ability, and survival upon chemotherapy independently of S100A4. An in vivo growth mouse model confirmed the importance of embigin and its cytoplasmic tail in mediating prostate tumor growth. Moreover, embigin and p21(WAF1) can be used to predict survival of prostate cancer patients. Our results demonstrated for the first time that the S100A4-embigin/AMPK/mTORC1/p21(WAF1) and NF-kappa B/MMP9 axis is a vital oncogenic molecular cascade for prostate cancer progression. We proposed that embigin and p21WAF1 could be used as prognostic biomarkers and a strategy to inhibit S100A4-embigin binding could be a therapeutic approach for prostate cancer patients.

    DOI: 10.3390/cancers10070239

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  • Stromal mesenchymal stem cells facilitate pancreatic cancer progression by regulating specific secretory molecules through mutual cellular interaction

    Ken Saito, Masakiyo Sakaguchi, Satoshi Maruyama, Hidekazu Iioka, Endy Widya Putranto, I. Wayan Sumardika, Nahoko Tomonobu, Takashi Kawasaki, Keiichi Homma, Eisaku Kondo

    JOURNAL OF CANCER   9 ( 16 )   2916 - 2929   2018年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:IVYSPRING INT PUBL  

    Pancreatic ductal adenocarcinoma (PDAC) is currently one of the most intractable malignancies with a typical scirrhous pattern in histology. Due to its abundant tumor stroma and scant vascularization, chemotherapeutic agents are considered inefficiently permeable to cancer nests, making it highly difficult to cure the patients with PDAC. However, PDAC is also considered to owe its intractability to other critical factors such as cellular interaction between tumor cells and tumor microenvironment as well as architectural barriers, which increases in therapeutic resistance. Here, we report a specific cellular interaction between PDAC cells and mesenchymal stem cells (MSCs) intermingled in PDAC stroma, which facilitates cancer invasion. Secretory phenotype profiling revealed that production of Amphiregulin (AREG) and MMP-3 were specifically upregulated under the coexistence of BxPC3 cells with human MSCs (approximately four to ten folds in AREG, and twenty to sixty-folds in MMP-3 compared to that of BxPC3 cells alone), whereas MMP-9 expression was decreased (less than one-tenth comparing with that of BxPC3 cells alone). Blockage of AREG production by its specific siRNA removed MSC-mediated driving force of BxPC3 invasiveness. Immunohistochemical analysis of tissue samples obtained both from PDAC patients and PDAC imitating mouse xenografted models revealed that significant coexpression of AREG and its receptor EGFR were detected on the cancer cells at invasive front. These results strongly suggested that cellular interaction between cancer cells and MSCs in the PDAC stroma might be critical to cancer progression, especially in the process of local invasion and the early stage development of metastasis.

    DOI: 10.7150/jca.24415

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  • Attenuation of CD4(+) CD25(+) Regulatory T Cells in the Tumor Microenvironment by Metformin, a Type 2 Diabetes Drug

    Yuki Kunisada, Shingo Eikawa, Nahoko Tomonobu, Shohei Domae, Takenori Uehara, Shohei Hori, Yukihiro Furusawa, Koji Hase, Akira Sasaki, Heiichiro Udono

    EBIOMEDICINE   25   154 - 164   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    CD4(+) CD25(+) regulatory T cells (Treg), an essential subset for preventing autoimmune diseases, is implicated as a negative regulator in anti-tumor immunity. Wefound thatmetformin (Met) reduced tumor-infiltrating Treg (Ti-Treg), particularly the terminally-differentiated CD103(+) KLRG1(+) population, and also decreased effector molecules such as CTLA4 and IL-10. Met inhibits the differentiation of naive CD4(+) T cells into inducible Treg (iTreg) by reducing forkhead box P3 (Foxp3) protein, caused by mTORC1 activation that was determined by the elevation of phosphorylated S6 (pS6), a downstream molecule of mTORC1. Rapamycin and compound C, an inhibitor of AMP-activated protein kinase (AMPK) restored the iTreg generation, further indicating the involvement of mTORC1 and AMPK. The metabolic profile of iTreg, increased Glut1-expression, and reduced mitochondrial membrane-potential and ROS production of Ti-Treg aided in identifying enhanced glycolysis upon Met-treatment. The negative impact of Met on Ti-Treg may help generation of the sustained antitumor immunity. (C) 2017 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license

    DOI: 10.1016/j.ebiom.2017.10.009

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  • Metformin-dependent metabolic reprogramming contributes to efficient anti-tumor immunity.

    Nahoko Tomonobu, Shingo Eikawa, Heiichiro Udono

    Nihon rinsho. Japanese journal of clinical medicine   75 ( 2 )   323 - 328   2017年2月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

    The rate of cancer incidence and mortality of Type 2 diabetes patients who were taking metformin seem to be decreased, comparing with those taking other drugs. We recently pro- vided compelling evidence showing that the effect might be mediated by immune system, thus, the reversion of exhausted tumor infiltrating CD8T lymphocytes (CD8TIL). Glycolysis is essential in CD8T cell function. However, the metabolism of CD8TIL is locked in a state of oxidative phosphorylation (OxPhos) dominant over glycolysis because of interaction between immune checkpoints and their ligands, and because of extremely low concentration of glu- cose in tumor microenvironment. Metformin increases the glycolysis efficiency, resulting in the conversion of CD8TIL to more active effector memory to fight against cancers.

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受賞

  • 奨励賞

    2021年9月   日本組織培養学会第93回大会  

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共同研究・競争的資金等の研究

  • Ad-REIC の新展開:REICタンパク質による免疫チェックポイント制御

    公益財団法人 両備てい園記念財団 

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    担当区分:研究代表者 

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  • S100A8/A9によるがんの脳指向性転移の機構解明とその制御

    公益財団法人 岡山医学振興会 

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    担当区分:研究代表者 

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