Updated on 2024/03/13

写真a

 
FUJIMURA Atsushi
 
Organization
Faculty of Medicine, Dentistry and Pharmaceutical Sciences Assistant Professor
Position
Assistant Professor
External link

Degree

  • 博士(医学) ( 岡山大学 )

Research Interests

  • プレシジョン・メディシンBNCT

  • tRNAエピトランスクリプトーム創薬

  • 翻訳機構を標的とした制がん戦略

  • タンパク質合成の分子機構

Research Areas

  • Life Science / Tumor biology

Education

  • Okayama University   大学院医歯薬学総合研究科   博士課程

    2009.4 - 2012.9

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    Country: Japan

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  • Okayama University   医学部   医学科

    2003.4 - 2009.3

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    Country: Japan

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Research History

  • Okayama University   Graduate School of Medicine , Dentistry and Pharmaceutical Sciences   Assistant Professor

    2017.4

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    Country:Japan

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  • Kumamoto University   Faculty of Life Sciences

    2015.6 - 2017.3

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    Country:Japan

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  • Padova University   Molecular Medicine

    2013.6 - 2015.5

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    Country:Italy

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  • Padova University   Molecular Medicine   Researcher

    2013.2 - 2013.5

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    Country:Italy

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  • Kumamoto University   Faculty of Life Sciences

    2012.10 - 2013.1

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Professional Memberships

Committee Memberships

  • 岡山大学   共同実験室運営委員会  

    2020.4   

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  • 岡山大学   医学科カリキュラム委員会  

    2020.4   

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  • Frontiers in Oncology   Guest Editor  

    2019   

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  • 岡山大学   基礎・社会医学系教育企画委員会  

    2018   

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Papers

  • Role of catecholamine synthases in the maintenance of cancer stem‐like cells in malignant peripheral nerve sheath tumors Reviewed

    Haruyoshi Katayama, Atsushi Fujimura, Rongsheng Huang, Yusuke Otani, Takuto Itano, Tomohiro Fujiwara, Toshiyuki Kunisada, Eiji Nakata, Toshifumi Ozaki

    Cancer Science   2024.1

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

    DOI: 10.1111/cas.16077

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  • Connective tissue mast cells store and release noradrenaline. Reviewed

    Yusuke Otani, Soichiro Yoshikawa, Kei Nagao, Takehiro Tanaka, Shinichi Toyooka, Atsushi Fujimura

    The journal of physiological sciences : JPS   73 ( 1 )   24 - 24   2023.10

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

    Mast cells are present in mucosal and connective tissues throughout the body. They synthesize and release a wide variety of bioactive molecules, such as histamine, proteases, and cytokines. In this study, we found that a population of connective tissue mast cells (CTMCs) stores and releases noradrenaline, originating from sympathetic nerves. Noradrenaline-storing cells, not neuronal fibers, were predominantly identified in the connective tissues of the skin, mammary gland, gastrointestinal tract, bronchus, thymus, and pancreas in wild-type mice but were absent in mast cell-deficient W-sash c-kit mutant KitW-sh/W-sh mice. In vitro studies using bone marrow-derived mast cells revealed that extracellular noradrenaline was taken up but not synthesized. Upon ionomycin stimulation, noradrenaline was released. Electron microscopy analyses further suggested that noradrenaline is stored in and released from the secretory granules of mast cells. Finally, we found that noradrenaline-storing CTMCs express organic cation transporter 3 (Oct3), which is also known as an extraneuronal monoamine transporter, SLC22A3. Our findings indicate that mast cells may play a role in regulating noradrenaline concentration by storing and releasing it in somatic tissues.

    DOI: 10.1186/s12576-023-00883-3

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  • Particle and Heavy Ion Transport Code System‐Based Microdosimetry for the Development of Boron Agents for Boron Neutron Capture Therapy Reviewed

    Takafumi Shigehira, Tadashi Hanafusa, Kazuyo Igawa, Tomonari Kasai, Shuichi Furuya, Hisakazu Nishimori, Yoshinobu Maeda, Hiroyuki Michiue, Atsushi Fujimura

    Advanced Theory and Simulations   2023.7

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    Authorship:Last author, Corresponding author   Publishing type:Research paper (scientific journal)  

    DOI: 10.1002/adts.202300163

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  • CDKAL1 Drives the Maintenance of Cancer Stem-Like Cells by Assembling the eIF4F Translation Initiation Complex. Reviewed International journal

    Rongsheng Huang, Takahiro Yamamoto, Eiji Nakata, Toshifumi Ozaki, Kazuhiko Kurozumi, Fanyan Wei, Kazuhito Tomizawa, Atsushi Fujimura

    Advanced Science (Weinheim, Baden-Wurttemberg, Germany)   e2206542   2023.2

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    Cancer stem-like cells (CSCs) have a unique translation mode, but little is understood about the process of elongation, especially the contribution of tRNA modifications to the maintenance of CSCs properties. Here, it is reported that, contrary to the initial aim, a tRNA-modifying methylthiotransferase CDKAL1 promotes CSC-factor SALL2 synthesis by assembling the eIF4F translation initiation complex. CDKAL1 expression is upregulated in patients with worse prognoses and is essential for maintaining CSCs in rhabdomyosarcoma (RMS) and common cancers. Translatome analysis reveals that a group of mRNAs whose translation is CDKAL1-dependent contains cytosine-rich sequences in the 5' untranslated region (5'UTR). Mechanistically, CDKAL1 promotes the translation of such mRNAs by organizing the eIF4F translation initiation complex. This complex formation does not require the enzyme activity of CDKAL1 but requires only the NH2 -terminus domain of CDKAL1. Furthermore, sites in CDKAL1 essential for forming the eIF4F complex are identified and discovered candidate inhibitors of CDKAL1-dependent translation.

    DOI: 10.1002/advs.202206542

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  • Adrenergic signaling promotes the expansion of cancer stem-like cells of malignant peripheral nerve sheath tumors Reviewed

    Rongsheng Huang, Atsushi Fujimura, Eiji Nakata, Shota Takihira, Hirofumi Inoue, Soichiro Yoshikawa, Takeshi Hiyama, Toshifumi Ozaki, Atsunori Kamiya

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   557   199 - 205   2021.6

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    Authorship:Lead author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Malignant peripheral nerve sheath tumor (MPNST), a highly malignant tumor that arises in peripheral nerve tissues, is known to be highly resistant to radiation and chemotherapy. Although there are several reports on genetic mutations and epigenetic changes that define the pathogenesis of MPNST, there is insufficient information regarding the microenvironment that contributes to the malignancy of MPNST. In the present study, we demonstrate that adrenaline increases the cancer stem cell population in MPNST. This effect is mediated by adrenaline stimulation of beta-2 adrenergic receptor (ADRB2), which activates the Hippo transducer, YAP/TAZ. Inhibition and RNAi experiments revealed that inhibition of ADRB2 attenuated the adrenaline-triggered activity of YAP/TAZ and subsequently attenuated MPNST cells stemness. Furthermore, ADRB2-YAP/TAZ axis was confirmed in the MPNST patients' specimens. The prognosis of patients with high levels of ADRB2 was found to be significantly worse. These data show that adrenaline exacerbates MPNST prognosis and may aid the development of new treatment strategies for MPNST.(c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

    DOI: 10.1016/j.bbrc.2021.03.172

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  • Differentiated glioblastoma cells accelerate tumor progression by shaping the tumor microenvironment via CCN1-mediated macrophage infiltration. Reviewed International journal

    Atsuhito Uneda, Kazuhiko Kurozumi, Atsushi Fujimura, Kentaro Fujii, Joji Ishida, Yosuke Shimazu, Yoshihiro Otani, Yusuke Tomita, Yasuhiko Hattori, Yuji Matsumoto, Nobushige Tsuboi, Keigo Makino, Shuichiro Hirano, Atsunori Kamiya, Isao Date

    Acta neuropathologica communications   9 ( 1 )   29 - 29   2021.2

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:BMC  

    Glioblastoma (GBM) is the most lethal primary brain tumor characterized by significant cellular heterogeneity, namely tumor cells, including GBM stem-like cells (GSCs) and differentiated GBM cells (DGCs), and non-tumor cells such as endothelial cells, vascular pericytes, macrophages, and other types of immune cells. GSCs are essential to drive tumor progression, whereas the biological roles of DGCs are largely unknown. In this study, we focused on the roles of DGCs in the tumor microenvironment. To this end, we extracted DGC-specific signature genes from transcriptomic profiles of matched pairs of in vitro GSC and DGC models. By evaluating the DGC signature using single cell data, we confirmed the presence of cell subpopulations emulated by in vitro culture models within a primary tumor. The DGC signature was correlated with the mesenchymal subtype and a poor prognosis in large GBM cohorts such as The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project. In silico signaling pathway analysis suggested a role of DGCs in macrophage infiltration. Consistent with in silico findings, in vitro DGC models promoted macrophage migration. In vivo, coimplantation of DGCs and GSCs reduced the survival of tumor xenograft-bearing mice and increased macrophage infiltration into tumor tissue compared with transplantation of GSCs alone. DGCs exhibited a significant increase in YAP/TAZ/TEAD activity compared with GSCs. CCN1, a transcriptional target of YAP/TAZ, was selected from the DGC signature as a candidate secreted protein involved in macrophage recruitment. In fact, CCN1 was secreted abundantly from DGCs, but not GSCs. DGCs promoted macrophage migration in vitro and macrophage infiltration into tumor tissue in vivo through secretion of CCN1. Collectively, these results demonstrate that DGCs contribute to GSC-dependent tumor progression by shaping a mesenchymal microenvironment via CCN1-mediated macrophage infiltration. This study provides new insight into the complex GBM microenvironment consisting of heterogeneous cells.

    DOI: 10.1186/s40478-021-01124-7

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  • Single-cell analyses reveal YAP/TAZ as regulators of stemness and cell plasticity in Glioblastoma. Reviewed International journal

    Martina Castellan, Alberto Guarnieri, Atsushi Fujimura, Francesca Zanconato, Giusy Battilana, Tito Panciera, Hanna Lucie Sladitschek, Paolo Contessotto, Anna Citron, Andrea Grilli, Oriana Romano, Silvio Bicciato, Matteo Fassan, Elena Porcù, Antonio Rosato, Michelangelo Cordenonsi, Stefano Piccolo

    Nature cancer   2 ( 2 )   174 - 188   2021.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:SPRINGERNATURE  

    Glioblastoma (GBM) is a devastating human malignancy. GBM stem-like cells (GSCs) drive tumor initiation and progression. Yet, the molecular determinants defining GSCs in their native state in patients remain poorly understood. Here we used single cell datasets and identified GSCs at the apex of the differentiation hierarchy of GBM. By reconstructing the GSCs' regulatory network, we identified the YAP/TAZ coactivators as master regulators of this cell state, irrespectively of GBM subtypes. YAP/TAZ are required to install GSC properties in primary cells downstream of multiple oncogenic lesions, and required for tumor initiation and maintenance in vivo in different mouse and human GBM models. YAP/TAZ act as main roadblock of GSC differentiation and their inhibition irreversibly lock differentiated GBM cells into a non-tumorigenic state, preventing plasticity and regeneration of GSC-like cells. Thus, GSC identity is linked to a key molecular hub integrating genetics and microenvironmental inputs within the multifaceted biology of GBM.

    DOI: 10.1038/s43018-020-00150-z

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  • In Vitro Studies to Define the Cell-Surface and Intracellular Targets of Polyarginine-Conjugated Sodium Borocaptate as a Potential Delivery Agent for Boron Neutron Capture Therapy. Reviewed International journal

    Atsushi Fujimura, Seiji Yasui, Kazuyo Igawa, Ai Ueda, Kaori Watanabe, Tadashi Hanafusa, Yasuaki Ichikawa, Sachiko Yoshihashi, Kazuki Tsuchida, Atsunori Kamiya, Shuichi Furuya

    Cells   9 ( 10 )   2020.9

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

    Boron neutron capture therapy (BNCT) requires pharmaceutical innovations and molecular-based evidence of effectiveness to become a standard cancer therapeutic in the future. Recently, in Japan, 4-borono-L-phenylalanine (BPA) was approved as a boron agent for BNCT against head and neck (H&N) cancers. H&N cancer appears to be a suitable target for BPA-BNCT, because the expression levels of L-type amino acid transporter 1 (LAT1), one of the amino acid transporters responsible for BPA uptake, are elevated in most cases of H&N cancer. However, in other types of cancer including malignant brain tumors, LAT1 is not always highly expressed. To expand the possibility of BNCT for these cases, we previously developed poly-arginine peptide (polyR)-conjugated mercaptoundecahydrododecaborate (BSH). PolyR confers the cell membrane permeability and tumor selectivity of BSH. However, the molecular determinants for the properties are not fully understood. In this present study, we have identified the cluster of differentiation 44 (CD44) protein and translational machinery proteins as a major cell surface target and intracellular targets of BSH-polyR, respectively. CD44, also known as a stem cell-associated maker in various types of cancer, is required for the cellular uptake of polyR-conjugated molecules. We showed that BSH-polyR was predominantly delivered to a CD44High cell population of cancer cells. Once delivered, BSH-polyR interacted with the translational machinery components, including the initiation factors, termination factors, and poly(A)-biding protein (PABP). As a proof of principle, we performed BSH-polyR-based BNCT against glioma stem-like cells and revealed that BSH-polyR successfully induced BNCT-dependent cell death specifically in CD44High cells. Bioinformatics analysis indicated that BSH-polyR would be suitable for certain types of malignant tumors. Our results shed light on the biochemical properties of BSH-polyR, which may further contribute to the therapeutic optimization of BSH-BNCT in the future.

    DOI: 10.3390/cells9102149

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  • 2-Methylthio Conversion of N6-Isopentenyladenosine in Mitochondrial tRNAs by CDK5RAP1 Promotes the Maintenance of Glioma-Initiating Cells. Reviewed International journal

    Takahiro Yamamoto, Atsushi Fujimura, Fan-Yan Wei, Naoki Shinojima, Jun-Ichiro Kuroda, Akitake Mukasa, Kazuhito Tomizawa

    iScience   21   42 - 56   2019.11

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    Authorship:Lead author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:CELL PRESS  

    2-Methylthio-N6-isopentenyl modification of adenosine (ms2i6A) is an evolutionally conserved modification found in mitochondrial (mt)-tRNAs. Cdk5 regulatory subunit-associated protein 1 (CDK5RAP1) specifically converts N6-isopentenyladenosine (i6A) to ms2i6A at position A37 of four mt-DNA-encoded tRNAs, and the modification regulates efficient mitochondrial translation and energy metabolism in mammals. Here, we report that the ms2 conversion mediated by CDK5RAP1 in mt-tRNAs is required to sustain glioma-initiating cell (GIC)-related traits. CDK5RAP1 maintained the self-renewal capacity, undifferentiated state, and tumorigenic potential of GICs. This regulation was not related to the translational control of mt-proteins. CDK5RAP1 abrogated the antitumor effect of i6A by converting i6A to ms2i6A and protected GICs from excessive autophagy triggered by i6A. The elevated activity of CDK5RAP1 contributed to the amelioration of the tumor-suppressive effect of i6A and promoted GIC maintenance. This work demonstrates that CDK5RAP1 is crucial for the detoxification of endogenous i6A and that GICs readily utilize this mechanism for survival.

    DOI: 10.1016/j.isci.2019.10.012

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  • Induction of Expandable Tissue-Specific Stem/Progenitor Cells through Transient Expression of YAP/TAZ. Reviewed International journal

    Tito Panciera, Luca Azzolin, Atsushi Fujimura, Daniele Di Biagio, Chiara Frasson, Silvia Bresolin, Sandra Soligo, Giuseppe Basso, Silvio Bicciato, Antonio Rosato, Michelangelo Cordenonsi, Stefano Piccolo

    Cell stem cell   19 ( 6 )   725 - 737   2016.12

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    The ability to induce autologous tissue-specific stem cells in culture could have a variety of applications in regenerative medicine and disease modeling. Here we show that transient expression of exogenous YAP or its closely related paralogue TAZ in primary differentiated mouse cells can induce conversion to a tissue-specific stem/progenitor cell state. Differentiated mammary gland, neuronal, and pancreatic exocrine cells, identified using a combination of cell sorting and lineage tracing approaches, efficiently convert to proliferating cells with properties of stem/progenitor cells of their respective tissues after YAP induction. YAP-induced mammary stem/progenitor cells show molecular and functional properties similar to endogenous MaSCs, including organoid formation and mammary gland reconstitution after transplantation. Because YAP/TAZ function is also important for self-renewal of endogenous stem cells in culture, our findings have implications for understanding the molecular determinants of the somatic stem cell state.

    DOI: 10.1016/j.stem.2016.08.009

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  • 翻訳制御機構を標的とした横紋筋肉腫の新規治療法の開発

    板野 拓人, 中田 英二, 藤村 篤史, 黄 栄生, 片山 晴喜, 藤原 智洋, 国定 俊之, 尾崎 敏文

    日本整形外科学会雑誌   97 ( 8 )   S1884 - S1884   2023.8

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    Language:Japanese   Publisher:(公社)日本整形外科学会  

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  • MPNST腫瘍細胞内のカテコラミン合成経路の阻害ががん幹細胞性に与える影響と治療薬としての可能性

    片山 晴喜, 藤村 篤史, 中田 英二, 板野 拓人, 藤原 智洋, 国定 俊之, 尾崎 敏文

    日本整形外科学会雑誌   97 ( 8 )   S1884 - S1884   2023.8

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  • MPNST腫瘍細胞内のカテコラミン合成経路とその腫瘍幹細胞性維持に対する役割

    片山 晴喜, 藤村 篤史, 中田 英二, 板野 拓人, 藤原 智洋, 国定 俊之, 尾崎 敏文

    日本整形外科学会雑誌   97 ( 6 )   S1493 - S1493   2023.6

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  • 加速器中性子源を用いたBNCTの展開

    井川 和代, 道上 宏之, 藤村 篤史

    Medical Science Digest   49 ( 4 )   224 - 226   2023.4

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    Language:Japanese   Publisher:(株)ニュー・サイエンス社  

    がん細胞に集積したホウ素薬剤と放射線である中性子が反応して,がん細胞を細胞レベルで消滅させる"ホウ素中性子捕捉療法(BNCT)"は,がん周囲の正常細胞への影響が少なく機能温存できるため低侵襲がん治療として期待されています。特に周囲の脳組織に浸潤性に増殖する難治性の悪性脳腫瘍に対しては,わずか1回のBNCTの治療で正常脳を温存して治療効果が得られるためBNCTを組み合わせた集学的初期治療法に期待が高まっております。世界に先駆けて日本では2020年より切除不能な局所再発頭頸部扁平上皮がん又は切除不能な頭頸部非扁平上皮がんに対して臨床研究ではなく医療としてBNCTを受けることができるようになりました。今後,BNCTと他の治療を組み合わせた集学的がん治療により健やかで心豊かに生活できる社会を実現します。(著者抄録)

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  • MPNSTの癌幹細胞性維持に対する腫瘍内のアドレナリン合成酵素の役割

    片山 晴喜, 藤村 篤史, 中田 英二, 大谷 悠介, 藤原 智洋, 国定 俊之, 神谷 厚範, 尾崎 敏文

    日本整形外科学会雑誌   96 ( 8 )   S1768 - S1768   2022.9

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  • Self-assembling A6K peptide nanotubes as a mercaptoundecahydrododecaborate (BSH) delivery system for boron neutron capture therapy (BNCT). Reviewed International journal

    Hiroyuki Michiue, Mizuki Kitamatsu, Asami Fukunaga, Nobushige Tsuboi, Atsushi Fujimura, Hiroaki Matsushita, Kazuyo Igawa, Tomonari Kasai, Natsuko Kondo, Hideki Matsui, Shuichi Furuya

    Journal of controlled release : official journal of the Controlled Release Society   330   788 - 796   2021.2

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:ELSEVIER  

    Boron neutron capture therapy (BNCT) is a tumor selective therapy, the effectiveness of which depends on sufficient 10B delivery to and accumulation in tumors. In this study, we used self-assembling A6K peptide nanotubes as boron carriers and prepared new boron agents by simple mixing of A6K and BSH. BSH has been used to treat malignant glioma patients in clinical trials and its drug safety and availability have been confirmed; however, its contribution to BNCT efficacy is low. A6K nanotube delivery improved two major limitations of BSH, including absence of intracellular transduction and non-specific drug delivery to tumor tissue. Varying the A6K peptide and BSH mixture ratio produced materials with different morphologies-determined by electron microscopy-and intracellular transduction efficiencies. We investigated the A6K/BSH 1:10 mixture ratio and found high intracellular boron uptake with no toxicity. Microscopy observation showed intracellular localization of A6K/BSH in the perinuclear region and endosome in human glioma cells. The intracellular boron concentration using A6K/BSH was almost 10 times higher than that of BSH. The systematic administration of A6K/BSH via mouse tail vein showed tumor specific accumulation in a mouse brain tumor model with immunohistochemistry and pharmacokinetic study. Neutron irradiation of glioma cells treated with A6K/BSH showed the inhibition of cell proliferation in a colony formation assay. Boron delivery using A6K peptide provides a unique and simple strategy for next generation BNCT drugs.

    DOI: 10.1016/j.jconrel.2020.11.001

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  • Sympathetic and parasympathetic innervation in cancer: therapeutic implications. Reviewed International journal

    Atsunori Kamiya, Takeshi Hiyama, Atsushi Fujimura, Soichiro Yoshikawa

    Clinical autonomic research : official journal of the Clinical Autonomic Research Society   31 ( 2 )   165 - 178   2020.9

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:SPRINGER HEIDELBERG  

    PURPOSE: The autonomic nervous system, consisting of sympathetic and parasympathetic/vagal nerves, is known to control the functions of any organ, maintaining whole-body homeostasis under physiological conditions. Recently, there has been increasing evidence linking sympathetic and parasympathetic/vagal nerves to cancers. The present review aimed to summarize recent developments from studies addressing the relationship between sympathetic and parasympathetic/vagal nerves and cancer behavior. METHODS: Literature review. RESULTS: Human and animal studies have revealed that sympathetic and parasympathetic/vagal nerves innervate the cancer microenvironment and alter cancer behavior. The sympathetic nerves have cancer-promoting effects on prostate cancer, breast cancer, and melanoma. On the other hand, while the parasympathetic/vagal nerves have cancer-promoting effects on prostate, gastric, and colorectal cancers, they have cancer-suppressing effects on breast and pancreatic cancers. These neural effects may be mediated by β-adrenergic or muscarinic receptors and can be explained by changes in cancer cell behavior, angiogenesis, tumor-associated macrophages, and adaptive antitumor immunity. CONCLUSIONS: Sympathetic nerves innervating the tumor microenvironment promote cancer progression and are related to stress-induced cancer behavior. The parasympathetic/vagal nerves have variable (promoting or suppressing) effects on different cancer types. Approaches directed toward the sympathetic and parasympathetic/vagal nerves can be developed as a new cancer therapy. In addition to existing pharmacological, surgical, and electrical approaches, a recently developed virus vector-based genetic local neuroengineering technology is a powerful approach that selectively manipulates specific types of nerve fibers innervating the cancer microenvironment and leads to the suppression of cancer progression. This technology will enable the creation of "cancer neural therapy" individually tailored to different cancer types.

    DOI: 10.1007/s10286-020-00724-y

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  • 分化型膠芽腫細胞はCCN1の分泌を介して腫瘍微小環境を改変する

    畝田 篤仁, 黒住 和彦, 藤村 篤史, 藤井 謙太郎, 島津 洋介, 松本 悠司, 坪井 伸成, 牧野 圭悟, 神谷 厚範, 伊達 勲

    Brain Tumor Pathology   37 ( Suppl. )   092 - 092   2020.8

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    Language:Japanese   Publisher:日本脳腫瘍病理学会  

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  • 分化型膠芽腫細胞はCCN1の分泌を介して腫瘍微小環境を改変する

    畝田 篤仁, 黒住 和彦, 藤村 篤史, 藤井 謙太郎, 島津 洋介, 松本 悠司, 坪井 伸成, 牧野 圭悟, 神谷 厚範, 伊達 勲

    Brain Tumor Pathology   37 ( Suppl. )   092 - 092   2020.8

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  • 細胞内局在を標的とした新規ホウ素製剤が切り拓く次世代BNCT

    藤村 篤史, 井川 和代, 植田 愛, 渡辺 香里, 道上 宏之, 市川 康明, 古矢 修一

    Medical Science Digest   46 ( 8 )   535 - 537   2020.7

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    病院設置型のBPA-BNCT治療システムがいよいよ社会実装されるに至った。今後BNCTががん治療法の一端を担うことになると広く期待されているが、一方で、現行のホウ素薬剤BPAによるホウ素送達が適していないがん種や症例に対しては、異なるメカニズムを有した新たなホウ素製剤の開発が必要である。BPA-BNCTは、F-BPAを用いたPET検査により適応可否が判断できる治療システムであるが、後続するホウ素製剤においても同様に患者層別化が可能であることが求められる。本稿では、我々が最近開発に取り組んでいるBSH製剤を例に、これからのホウ素製剤を用いたBNCTが患者層別化可能な治療法であるためには、どのような観点から開発に取り組むべきかを考察したい。(著者抄録)

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  • Annexin A2-STAT3-Oncostatin M receptor axis drives phenotypic and mesenchymal changes in glioblastoma. Reviewed International journal

    Yuji Matsumoto, Tomotsugu Ichikawa, Kazuhiko Kurozumi, Yoshihiro Otani, Atsushi Fujimura, Kentaro Fujii, Yusuke Tomita, Yasuhiko Hattori, Atsuhito Uneda, Nobushige Tsuboi, Keisuke Kaneda, Keigo Makino, Isao Date

    Acta neuropathologica communications   8 ( 1 )   42 - 42   2020.4

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    Glioblastoma (GBM) is characterized by extensive tumor cell invasion, angiogenesis, and proliferation. We previously established subclones of GBM cells with distinct invasive phenotypes and identified annexin A2 (ANXA2) as an activator of angiogenesis and perivascular invasion. Here, we further explored the role of ANXA2 in regulating phenotypic transition in GBM. We identified oncostatin M receptor (OSMR) as a key ANXA2 target gene in GBM utilizing microarray analysis and hierarchical clustering analysis of the Ivy Glioblastoma Atlas Project and The Cancer Genome Atlas datasets. Overexpression of ANXA2 in GBM cells increased the expression of OSMR and phosphorylated signal transducer and activator of transcription 3 (STAT3) and enhanced cell invasion, angiogenesis, proliferation, and mesenchymal transition. Silencing of OSMR reversed the ANXA2-induced phenotype, and STAT3 knockdown reduced OSMR protein expression. Exposure of GBM cells to hypoxic conditions activated the ANXA2-STAT3-OSMR signaling axis. Mice bearing ANXA2-overexpressing GBM exhibited shorter survival times compared with control tumor-bearing mice, whereas OSMR knockdown increased the survival time and diminished ANXA2-mediated tumor invasion, angiogenesis, and growth. Further, we uncovered a significant relationship between ANXA2 and OSMR expression in clinical GBM specimens, and demonstrated their correlation with tumor histopathology and patient prognosis. Our results indicate that the ANXA2-STAT3-OSMR axis regulates malignant phenotypic changes and mesenchymal transition in GBM, suggesting that this axis is a promising therapeutic target to treat GBM aggressiveness.

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  • Intracranial Mesenchymal Chondrosarcoma Lacking the Typical Histopathological Features Diagnosed by HEY1-NCOA2 Gene Fusion. Reviewed

    Atsuhito Uneda, Kazuhiko Kurozumi, Atsushi Fujimura, Atsunori Kamiya, Takanori Hirose, Hiroyuki Yanai, Isao Date

    NMC case report journal   7 ( 2 )   47 - 52   2020.4

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    Intracranial mesenchymal chondrosarcoma (MCS) is a rare neoplasm. The diagnosis of MCS is confirmed by the presence of a biphasic pattern on histological examination, comprising undifferentiated small round cells admixed with islands of well-differentiated hyaline cartilage; however, a differential diagnosis may be challenging in some cases. A 28-year-old woman with a 2-month history of headache was referred to our hospital. Radiologic studies showed an extra-axial lobulated mass composed of calcified and uncalcified areas occupying the left middle fossa. Surgical resection was planned, but her headache suddenly worsened before her planned hospital admission and she was admitted as an emergency. Radiologic studies showed an acute hemorrhage in the uncalcified part of the mass. The mass was resected via the left zygomatic approach after embolization of the feeder vessels. The most likely histopathological diagnosis was MCS. However, the typical bimorphic pattern was not identified in our surgical samples; each undifferentiated area and well-differentiated area was observed separately in different tissue specimens, and no islands of well-differentiated hyaline cartilage were identified within the undifferentiated areas in the same specimen. Molecular assays confirmed the presence of HEY1-NCOA2 fusion. IRF2BP2-CDX1 fusion and IDH1/2 mutations were negative. The final diagnosis of MCS was made based on the presence of HEY1-NCOA2 gene fusion. MCS should be included in the differential diagnosis when radiologic studies show an extra-axial lobulated mass with calcification. Furthermore, molecular demonstration of HEY1-NCOA2 gene fusion may help make a precise diagnosis of MCS, especially in surgical samples lacking the typical histopathological features.

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  • Editorial: The Role of Epigenetic Modifications in Cancer Progression. International journal

    Atsushi Fujimura, Hailong Pei, Hongquan Zhang, Hanna Lucie Sladitschek, Lei Chang

    Frontiers in oncology   10   617178 - 617178   2020

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  • AN ANNEXIN A2-REGULATED PHENOTYPIC SHIFT IN GLIOMA

    Yuji Matsumoto, Tomotsugu Ichikawa, Kazuhiko Kurozumi, Yoshihiro Otani, Atsushi Fujimura, Kentaro Fujii, Yosuke Shimazu, Yusuke Tomita, Yasuhiko Hattori, Atsuhito Uneda, Nobushige Tsuboi, Keisuke Kaneda, Keigo Makino, Isao Date

    NEURO-ONCOLOGY   21   31 - 32   2019.11

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  • tRNA修飾酵素CDK5RAP1は膠芽腫幹細胞様細胞に重要である(Detoxification of N6-isopentenyladenosine by Cdk5rap1 controls the cell fate of glioma initiating cells)

    山本 隆広, 藤村 篤史, 魏 范研, 篠島 直樹, 黒田 順一郎, 武笠 晃丈, 富澤 一仁

    日本癌学会総会記事   78回   P - 3054   2019.9

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  • Matricellular protein CCN1による悪性神経膠腫進展の分子メカニズム

    畝田 篤仁, 黒住 和彦, 藤村 篤史, 藤井 謙太郎, 冨田 祐介, 服部 靖彦, 松本 悠司, 坪井 伸成, 神谷 厚範, 伊達 勲

    Brain Tumor Pathology   36 ( Suppl. )   083 - 083   2019.5

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  • Annexin A2の発現変化により規定されるグリオーマ表現型シフトの分子機序解明

    松本 悠司, 市川 智継, 黒住 和彦, 大谷 理浩, 藤村 篤史, 藤井 謙太郎, 冨田 祐介, 服部 靖彦, 畝田 篤人, 伊達 勲

    Brain Tumor Pathology   36 ( Suppl. )   083 - 083   2019.5

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  • Role of CCN1 induction by YAP/TAZ in malignant glioma

    Atsuhito Uneda, Kazuhiko Kurozumi, Atsushi Fujimura, Kentaro Fujii, Toshihiko Shimizu, Yusuke Tomita, Yasuhiko Hattori, Yuji Matsumoto, Nobunari Tsuboi, Isao Date

    BRAIN PATHOLOGY   29   192 - 192   2019.2

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  • NEW A6K BORON DRUG DELIVERY SYSTEM FOR CLINICAL APPLICATION OF BORON NEUTRON CAPTURE THERAPY (BNCT)

    Hiroyuki Michiue, Asami Fukunaga, Atsushi Fujimura, Kazuyo Igawa, Hideki Matsui, Shuichi Furuya

    NEURO-ONCOLOGY   20   73 - 73   2018.11

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  • 悪性神経膠腫におけるYAP/TAZによるCCN1発現誘導の役割

    畝田 篤仁, 黒住 和彦, 藤村 篤史, 藤井 謙太郎, 清水 俊彦, 冨田 祐介, 服部 靖彦, 松本 悠司, 坪井 伸成, 伊達 勲

    Brain Tumor Pathology   35 ( Suppl. )   140 - 140   2018.9

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  • Defective Mitochondrial tRNA Taurine Modification Activates Global Proteostress and Leads to Mitochondrial Disease. Reviewed International journal

    Md Fakruddin, Fan-Yan Wei, Takeo Suzuki, Kana Asano, Takashi Kaieda, Akiko Omori, Ryoma Izumi, Atsushi Fujimura, Taku Kaitsuka, Keishi Miyata, Kimi Araki, Yuichi Oike, Luca Scorrano, Tsutomu Suzuki, Kazuhito Tomizawa

    Cell reports   22 ( 2 )   482 - 496   2018.1

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    A subset of mitochondrial tRNAs (mt-tRNAs) contains taurine-derived modifications at 34U of the anticodon. Loss of taurine modification has been linked to the development of mitochondrial diseases, but the molecular mechanism is still unclear. Here, we showed that taurine modification is catalyzed by mitochondrial optimization 1 (Mto1) in mammals. Mto1 deficiency severely impaired mitochondrial translation and respiratory activity. Moreover, Mto1-deficient cells exhibited abnormal mitochondrial morphology owing to aberrant trafficking of nuclear DNA-encoded mitochondrial proteins, including Opa1. The mistargeted proteins were aggregated and misfolded in the cytoplasm, which induced cytotoxic unfolded protein response. Importantly, application of chemical chaperones successfully suppressed cytotoxicity by reducing protein misfolding and increasing functional mitochondrial proteins in Mto1-deficient cells and mice. Thus, our results demonstrate the essential role of taurine modification in mitochondrial translation and reveal an intrinsic protein homeostasis network between the mitochondria and cytosol, which has therapeutic potential for mitochondrial diseases.

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  • ANTI-DEPRESSANT, SSRI IDENTIFIED BY DRUG REPOSITIONING SYSTEM, BLOCKED GLIOBLASTOMA INVASION WITH TARGETING TO INHIBIT ACTIN POLYMERIZATION

    Hiroyuki Michiue, Keiichiro Hayashi, Atsushi Fujimura, Hiroaki Matsushita, Tei-ichi Nishiki, Hideki Matsui

    NEURO-ONCOLOGY   19   63 - 63   2017.11

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  • RNA修飾の代謝機構に関する研究

    森岡 太意気, 魏 范研, 藤村 篤史, 富澤 一仁

    日本生理学雑誌   79 ( 1 )   32 - 33   2017.2

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  • YAP/TAZによる組織特異的な体性幹細胞への脱分化誘導法の確立

    藤村 篤史, 富澤 一仁, ステファノ・ピッコロ

    日本生理学雑誌   79 ( 1 )   26 - 26   2017.2

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  • メッセンジャーRNA(mRNA)に存在するチオメチル化修飾の探索

    江村 修平, 魏 范研, 藤村 篤史, 富澤 一仁

    日本生理学雑誌   79 ( 1 )   30 - 31   2017.2

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  • Reactive sulfur species regulate tRNA methylthiolation and contribute to insulin secretion. Reviewed International journal

    Nozomu Takahashi, Fan-Yan Wei, Sayaka Watanabe, Mayumi Hirayama, Yuya Ohuchi, Atsushi Fujimura, Taku Kaitsuka, Isao Ishii, Tomohiro Sawa, Hideki Nakayama, Takaaki Akaike, Kazuhito Tomizawa

    Nucleic acids research   45 ( 1 )   435 - 445   2017.1

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    The 2-methylthio (ms2) modification at A37 of tRNAs is critical for accurate decoding, and contributes to metabolic homeostasis in mammals. However, the regulatory mechanism of ms2 modification remains largely unknown. Here, we report that cysteine hydropersulfide (CysSSH), a newly identified reactive sulfur species, is involved in ms2 modification in cells. The suppression of intracellular CysSSH production rapidly reduced ms2 modification, which was rescued by the application of an exogenous CysSSH donor. Using a unique and stable isotope-labeled CysSSH donor, we show that CysSSH was capable of specifically transferring its reactive sulfur atom to the cysteine residues of ms2-modifying enzymes as well as ms2 modification. Furthermore, the suppression of CysSSH production impaired insulin secretion and caused glucose intolerance in both a pancreatic β-cell line and mouse model. These results demonstrate that intracellular CysSSH is a novel sulfur source for ms2 modification, and that it contributes to insulin secretion.

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  • HDAC9 regulates the alternative lengthening of telomere (ALT) pathway via the formation of ALT-associated PML bodies. Reviewed International journal

    Mohd Raeed Jamiruddin, Taku Kaitsuka, Farzana Hakim, Atsushi Fujimura, Fan-Yan Wei, Hisato Saitoh, Kazuhito Tomizawa

    Biochemical and biophysical research communications   481 ( 1-2 )   25 - 30   2016.12

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    Cancer cells overcome cellular senescence by activating the telomere maintenance mechanism, which can be either through telomerase or the alternative lengthening of telomeres (ALT). Being exclusive to cancer cells, targeting ALT is a more promising route for the development of drugs against cancer. The histone deacetylase (HDAC) family plays significant roles in various cellular processes. In addition to the regulation of gene expression, HDACs are also known to directly interact with many proteins. We focused on this family, and found that HDAC9 was up-regulated in ALT-positive cells. In ALT-positive cells treated with HDAC9 siRNA, there was a decrease in the telomere replicative capacity, which was evident from the C-circles assay. Furthermore, the formation of ALT-associated promyelocytic leukemia (PML) nuclear bodies (APBs) was inhibited by HDAC9 knockdown. Based on this study, it is suggested that HDAC9 regulates the formation of APBs and could be a candidate for the target of ALT-cancer therapy.

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  • Mtu1-Mediated Thiouridine Formation of Mitochondrial tRNAs Is Required for Mitochondrial Translation and Is Involved in Reversible Infantile Liver Injury. Reviewed International journal

    Yong Wu, Fan-Yan Wei, Layla Kawarada, Takeo Suzuki, Kimi Araki, Yoshihiro Komohara, Atsushi Fujimura, Taku Kaitsuka, Motohiro Takeya, Yuichi Oike, Tsutomu Suzuki, Kazuhito Tomizawa

    PLoS genetics   12 ( 9 )   e1006355   2016.9

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    Reversible infantile liver failure (RILF) is a unique heritable liver disease characterized by acute liver failure followed by spontaneous recovery at an early stage of life. Genetic mutations in MTU1 have been identified in RILF patients. MTU1 is a mitochondrial enzyme that catalyzes the 2-thiolation of 5-taurinomethyl-2-thiouridine (τm5s2U) found in the anticodon of a subset of mitochondrial tRNAs (mt-tRNAs). Although the genetic basis of RILF is clear, the molecular mechanism that drives the pathogenesis remains elusive. We here generated liver-specific knockout of Mtu1 (Mtu1LKO) mice, which exhibited symptoms of liver injury characterized by hepatic inflammation and elevated levels of plasma lactate and AST. Mechanistically, Mtu1 deficiency resulted in a loss of 2-thiolation in mt-tRNAs, which led to a marked impairment of mitochondrial translation. Consequently, Mtu1LKO mice exhibited severe disruption of mitochondrial membrane integrity and a broad decrease in respiratory complex activities in the hepatocytes. Interestingly, mitochondrial dysfunction induced signaling pathways related to mitochondrial proliferation and the suppression of oxidative stress. The present study demonstrates that Mtu1-dependent 2-thiolation of mt-tRNA is indispensable for mitochondrial translation and that Mtu1 deficiency is a primary cause of RILF. In addition, Mtu1 deficiency is associated with multiple cytoprotective pathways that might prevent catastrophic liver failure and assist in the recovery from liver injury.

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  • 私はなぜ研究医を目指したか 文部科学省GPプログラムや他の取組みの検証 研究マインド涵養の場としてのARTプログラム

    藤村 篤史, 富澤 一仁, 松井 秀樹

    医学教育   47 ( Suppl. )   22 - 22   2016.7

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  • Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization. Reviewed International journal

    Keiichiro Hayashi, Hiroyuki Michiue, Hiroshi Yamada, Katsuyoshi Takata, Hiroki Nakayama, Fan-Yan Wei, Atsushi Fujimura, Hiroshi Tazawa, Akira Asai, Naohisa Ogo, Hiroyuki Miyachi, Tei-ichi Nishiki, Kazuhito Tomizawa, Kohji Takei, Hideki Matsui

    Scientific reports   6   23372 - 23372   2016.3

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    Glioblastoma multiforme (GBM) is the most common malignant brain tumor with a median survival time about one year. Invasion of GBM cells into normal brain is the major cause of poor prognosis and requires dynamic reorganization of the actin cytoskeleton, which includes lamellipodial protrusions, focal adhesions, and stress fibers at the leading edge of GBM. Therefore, we hypothesized that inhibitors of actin polymerization can suppress GBM migration and invasion. First, we adopted a drug repositioning system for screening with a pyrene-actin-based actin polymerization assay and identified fluvoxamine, a clinically used antidepressant. Fluvoxamine, selective serotonin reuptake inhibitor, was a potent inhibitor of actin polymerization and confirmed as drug penetration through the blood-brain barrier (BBB) and accumulation of whole brain including brain tumor with no drug toxicity. Fluvoxamine inhibited serum-induced ruffle formation, cell migration, and invasion of human GBM and glioma stem cells in vitro by suppressing both FAK and Akt/mammalian target of rapamycin signaling. Daily treatment of athymic mice bearing human glioma-initiating cells with fluvoxamine blocked tumor cell invasion and prolonged the survival with almost same dose of anti-depressant effect. In conclusion, fluvoxamine is a promising anti-invasive treatment against GBM with reliable approach.

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  • X染色体連鎖性精神遅滞の分子機構解明に関する研究

    永芳 友, 魏 范研, 貝塚 拓, 藤村 篤史, 平田 翔児, 鈴木 健夫, 鈴木 勉, 富澤 一仁

    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   88回・38回   [1T18p - 02(1P1278)]   2015.12

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  • CBIO-25NEW HYPOXIA-INDUCED INVASION FACTOR IN HUMAN GLIOBLASTOMA INVASION.

    Michiue H, Fujimura A, Mastushita H, Nishiki T, Matsui H

    Neuro-Oncology   2015.11

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  • Cdk5rap1-mediated 2-methylthio modification of mitochondrial tRNAs governs protein translation and contributes to myopathy in mice and humans. Reviewed International journal

    Fan-Yan Wei, Bo Zhou, Takeo Suzuki, Keishi Miyata, Yoshihiro Ujihara, Haruki Horiguchi, Nozomu Takahashi, Peiyu Xie, Hiroyuki Michiue, Atsushi Fujimura, Taku Kaitsuka, Hideki Matsui, Yasutoshi Koga, Satoshi Mohri, Tsutomu Suzuki, Yuichi Oike, Kazuhito Tomizawa

    Cell metabolism   21 ( 3 )   428 - 42   2015.3

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    Transfer RNAs (tRNAs) contain a wide variety of posttranscriptional modifications that are important for accurate decoding. Mammalian mitochondrial tRNAs (mt-tRNAs) are modified by nuclear-encoded tRNA-modifying enzymes; however, the physiological roles of these modifications remain largely unknown. In this study, we report that Cdk5 regulatory subunit-associated protein 1 (Cdk5rap1) is responsible for 2-methylthio (ms(2)) modifications of mammalian mt-tRNAs for Ser(UCN), Phe, Tyr, and Trp codons. Deficiency in ms(2) modification markedly impaired mitochondrial protein synthesis, which resulted in respiratory defects in Cdk5rap1 knockout (KO) mice. The KO mice were highly susceptive to stress-induced mitochondrial remodeling and exhibited accelerated myopathy and cardiac dysfunction under stressed conditions. Furthermore, we demonstrate that the ms(2) modifications of mt-tRNAs were sensitive to oxidative stress and were reduced in patients with mitochondrial disease. These findings highlight the fundamental role of ms(2) modifications of mt-tRNAs in mitochondrial protein synthesis and their pathological consequences in mitochondrial disease.

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  • Identification of a splicing variant that regulates type 2 diabetes risk factor CDKAL1 level by a coding-independent mechanism in human. Reviewed International journal

    Bo Zhou, Fan-Yan Wei, Narumi Kanai, Atsushi Fujimura, Taku Kaitsuka, Kazuhito Tomizawa

    Human molecular genetics   23 ( 17 )   4639 - 50   2014.9

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    Single-nucleotide polymorphisms (SNPs) in CDKAL1 have been associated with the development of type 2 diabetes (T2D). CDKAL1 catalyzes 2-methylthio modification of adenosine at position 37 of tRNA(Lys)(UUU). A deficit of this modification causes aberrant protein synthesis, and is associated with impairment of insulin secretion in both mouse model and human. However, it is unknown whether the T2D-associated SNPs in CDKAL1 are associated with downregulation of CDKAL1 by regulating the gene expression. Here, we report a specific splicing variant of CDKAL1 termed CDKAL1-v1 that is markedly lower in individuals carrying risk SNPs of CDKAL1. Interestingly, CDKAL1-v1 is a non-coding transcript, which regulates the CDKAL1 level by competitive binding to a CDKAL1-targeting miRNA. By direct editing of the genome, we further show that the nucleotides around the SNP regions are critical for the alternative splicing of CDKAL1-v1. These findings reveal that the T2D-associated SNPs in CDKAL1 reduce CDKAL1-v1 levels by impairing splicing, which in turn increases miRNA-mediated suppression of CDKAL1. Our results suggest that CDKAL1-v1-mediated suppression of CDKAL1 might underlie the pathogenesis of T2D in individuals carrying the risk SNPs.

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  • Cyclin G2 promotes hypoxia-driven local invasion of glioblastoma by orchestrating cytoskeletal dynamics. Reviewed International journal

    Atsushi Fujimura, Hiroyuki Michiue, Yan Cheng, Atsuhito Uneda, Yasunari Tani, Tei-ichi Nishiki, Tomotsugu Ichikawa, Fan-Yan Wei, Kazuhito Tomizawa, Hideki Matsui

    Neoplasia (New York, N.Y.)   15 ( 11 )   1272 - 81   2013.11

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    Microenvironmental conditions such as hypoxia potentiate the local invasion of malignant tumors including glioblastomas by modulating signal transduction and protein modification, yet the mechanism by which hypoxia controls cytoskeletal dynamics to promote the local invasion is not well defined. Here, we show that cyclin G2 plays pivotal roles in the cytoskeletal dynamics in hypoxia-driven invasion by glioblastoma cells. Cyclin G2 is a hypoxia-induced and cytoskeleton-associated protein and is required for glioblastoma expansion. Mechanistically, cyclin G2 recruits cortactin to the juxtamembrane through its SH3 domain-binding motif and consequently promotes the restricted tyrosine phosphorylation of cortactin in concert with src. Moreover, cyclin G2 interacts with filamentous actin to facilitate the formation of membrane ruffles. In primary glioblastoma, cyclin G2 is abundantly expressed in severely hypoxic regions such as pseudopalisades, which consist of actively migrating glioma cells. Furthermore, we show the effectiveness of dasatinib against hypoxia-driven, cyclin G2-involved invasion in vitro and in vivo. Our findings elucidate the mechanism of cytoskeletal regulation by which severe hypoxia promotes the local invasion and may provide a therapeutic target in glioblastoma.

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  • Clinicopathological characteristics of human epidermal growth factor receptor 2-positive Barrett's adenocarcinoma. Reviewed International journal

    Takehiro Tanaka, Atsushi Fujimura, Koichi Ichimura, Hiroyuki Yanai, Yasuharu Sato, Katsuyohi Takata, Hiroyuki Okada, Seiji Kawano, Shunsuke Tanabe, Tadashi Yoshino

    World journal of gastroenterology   18 ( 43 )   6263 - 8   2012.11

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    AIM: To compare the clinicopathological characteristics of human epidermal growth factor receptor 2 (HER2)-positive and HER2-negative Barrett's adenocarcinoma in Japan. METHODS: We performed immunohistochemical analysis of HER2 in 30 samples taken from patients with Barrett's adenocarcinoma and dual color in situ hybridization in cases showing 2+ reactions. We compared the clinicopathological characteristics of HER2-positive and HER2-negative patients. RESULTS: HER2 positivity was identified in 8 (27%) carcinoma samples. We found that HER2 expression was associated with p53 overexpression (100% vs 52.6% in pT1 tumor; 100% vs 54.5% in all stage tumor, P < 0.05) and protruding lesions at the early disease stage. There was no association between the mucin phenotype of the carcinomas and prognosis. HER2 expression and low clinical stage were unexpectedly different between Barrett's adenocarcinoma patients and gastric cancer patients, but the macroscopic features may be associated with earlier diagnosis in these patients. CONCLUSION: Our results suggest that HER2-positive Barrett's adenocarcinomas are associated with p53 overexpression and lesion protrusion at the early disease stage.

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  • Combining poly-arginine with the hydrophobic counter-anion 4-(1-pyrenyl)-butyric acid for protein transduction in transdermal delivery. Reviewed International journal

    Gerile Candan, Hiroyuki Michiue, Sanae Ishikawa, Atsushi Fujimura, Keiichiro Hayashi, Atsuhito Uneda, Akiko Mori, Iori Ohmori, Tei-ichi Nishiki, Hideki Matsui, Kazuhito Tomizawa

    Biomaterials   33 ( 27 )   6468 - 75   2012.9

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    Topical therapy is the most favored form of treatment for whitening against hyperpigmentation and sunburn because it lends itself to self-administration, patient compliance, and absence of systemic adverse effects. However, transdermal delivery of hydrophilic chemicals is difficult. The main purpose of this study is to develop a delivering system of hydrophilic drugs and proteins across the skin. Hydroquinone (HQ), a well-known tyrosinase inhibitor and antimelanogenesis compound, and enhanced green fluorescent protein (EGFP) were fused with eleven poly-arginine (11R). Both HQ-11R and EGFP-11R were efficiently delivered in B16 cells, a mouse melanoma cell line. HQ-11R was as effective as HQ alone at inhibiting melanin synthesis in B16 cells. EGFP-11R was efficiently delivered into cells of the epidermis with 4-(1-pyrenyl)-butyric acid (PB), a counteranion bearing an aromatic hydrophobic moiety, in vivo, but EGFP alone or EGFP-11R without PB was not. Finally, topical application of HQ-11R with PB significantly inhibited UV irradiation-induced pigmentation in guinea pigs compared with HQ alone. These results suggest that topical therapy using poly-arginine in combination with PB is useful for the delivery of hydrophilic drugs and proteins by the transdermal route.

    DOI: 10.1016/j.biomaterials.2012.04.056

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  • 恒常活性型カルシニューリンによる毛周期制御機構 新しい機構に基づく発毛促進ペプチドの開発

    藤村 篤史, 富澤 一仁, 松井 秀樹

    岡山医学会雑誌   124 ( 2 )   101 - 104   2012.8

  • A protein transduction method using oligo-arginine (3R) for the delivery of transcription factors into cell nuclei. Reviewed International journal

    Takashi Hitsuda, Hiroyuki Michiue, Mizuki Kitamatsu, Atsushi Fujimura, Feifei Wang, Takahiro Yamamoto, Xiao-Jian Han, Hiroshi Tazawa, Atsuhito Uneda, Iori Ohmori, Tei-ichi Nishiki, Kazuhito Tomizawa, Hideki Matsui

    Biomaterials   33 ( 18 )   4665 - 72   2012.6

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    Protein transduction with cell-penetrating peptides such as poly-arginine and HIV TAT peptides is widely used to deliver proteins, peptides, siRNA and biologically active compounds. It has been thought that poly-arginine peptides transduce proteins in a manner dependent on the number of arginine residues and oligo-peptides such as three arginines (3R) are ineffective. Here we showed that 3R-fused proteins were effectively delivered and functioned in cells co-treated with pyrenebutyrate, a counteranion bearing an aromatic hydrophobic moiety. Little 3R was transduced in glioma cells without pyrenebutyrate whereas the oligo-arginine was effectively delivered with pyrenebutyrate. Enhanced green fluorescence protein (eGFP) fused with 3R was effectively delivered into various kinds of cells including primary cultured cells and suspended cells in the presence of pyrenebutyrate. p53 fused with 3R (3R-p53) was delivered into glioma cells without pyrenebutyrate but could not be translocated into the nucleus. In contrast, 3R-p53 was observed in nuclei of glioma cells when co-applied with pyrenebutyrate. Although 3R-p53 was delivered less effectively than 11R-p53 with pyrenebutyrate, its transcriptional activity was higher than that of 11R-p53. Moreover, a single administration of 3R-p53 with pyrenebutyrate significantly inhibited the growth of cancer cells. These results suggest protein transduction using an oligo-arginine (3R) with pyrenebutyrate to be a good tool for the delivery of functional transcription factors and a promising method of treating cancer.

    DOI: 10.1016/j.biomaterials.2012.02.049

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  • Ca(2+)-independent syntaxin binding to the C(2)B effector region of synaptotagmin. Reviewed International journal

    Toshio Masumoto, Koichiro Suzuki, Iori Ohmori, Hiroyuki Michiue, Kazuhito Tomizawa, Atsushi Fujimura, Tei-ichi Nishiki, Hideki Matsui

    Molecular and cellular neurosciences   49 ( 1 )   1 - 8   2012.1

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    Although synaptotagmin I, which is a calcium (Ca(2+))-binding synaptic vesicle protein, may trigger soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated synaptic vesicle exocytosis, the mechanisms underlying the interaction between these proteins remain controversial, especially with respect to the identity of the protein(s) in the SNARE complex that bind(s) to synaptotagmin and whether Ca(2+) is required for their highly effective binding. To address these questions, native proteins were solubilized, immunoprecipitated from rat brain extracts, and analyzed by immunoblotting. SNARE complexes comprising syntaxin 1, 25-kDa synaptosomal-associated protein (SNAP-25), and synaptobrevin 2 were coprecipitated with synaptotagmin I in the presence of ethylene glycol tetraacetic acid. The amount of coprecipitated proteins was significantly unaltered by the addition of Ca(2+) to the brain extract. To identify the component of the SNARE complex that bound to synaptotagmin, SNARE was coexpressed with synaptotagmin in HEK293 cells and immunoprecipitated. Syntaxin, but not SNAP-25 and synaptobrevin, bound to synaptotagmin in a Ca(2+)-independent manner, and the binding was abolished in the presence of 1M NaCl. Synaptotagmin contains 2 Ca(2+)-binding domains (C(2)A, C(2)B). Mutating the positively charged lysine residues in the putative effector-binding region of the C(2)B domain, which are critical for transmitter release, markedly inhibited synaptotagmin-syntaxin binding, while similar mutations in the C(2)A domain had no effect on binding. Synaptotagmin-syntaxin binding was reduced by mutating multiple negatively charged glutamate residues in the amino-terminal half of the syntaxin SNARE motif. These results indicate that synaptotagmin I binds to syntaxin 1 electrostatically through its C(2)B domain effector region in a Ca(2+)-independent fashion, providing biochemical evidence that synaptotagmin I binds SNARE complexes before Ca(2+) influx into presynaptic nerve terminals.

    DOI: 10.1016/j.mcn.2011.09.007

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  • Deficit of tRNA(Lys) modification by Cdkal1 causes the development of type 2 diabetes in mice. Reviewed International journal

    Fan-Yan Wei, Takeo Suzuki, Sayaka Watanabe, Satoshi Kimura, Taku Kaitsuka, Atsushi Fujimura, Hideki Matsui, Mohamed Atta, Hiroyuki Michiue, Marc Fontecave, Kazuya Yamagata, Tsutomu Suzuki, Kazuhito Tomizawa

    The Journal of clinical investigation   121 ( 9 )   3598 - 608   2011.9

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    The worldwide prevalence of type 2 diabetes (T2D), which is caused by a combination of environmental and genetic factors, is increasing. With regard to genetic factors, variations in the gene encoding Cdk5 regulatory associated protein 1-like 1 (Cdkal1) have been associated with an impaired insulin response and increased risk of T2D across different ethnic populations, but the molecular function of this protein has not been characterized. Here, we show that Cdkal1 is a mammalian methylthiotransferase that biosynthesizes 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A) in tRNA(Lys)(UUU) and that it is required for the accurate translation of AAA and AAG codons. Mice with pancreatic β cell-specific KO of Cdkal1 (referred to herein as β cell KO mice) showed pancreatic islet hypertrophy, a decrease in insulin secretion, and impaired blood glucose control. In Cdkal1-deficient β cells, misreading of Lys codon in proinsulin occurred, resulting in a reduction of glucose-stimulated proinsulin synthesis. Moreover, expression of ER stress-related genes was upregulated in these cells, and abnormally structured ER was observed. Further, the β cell KO mice were hypersensitive to high fat diet-induced ER stress. These findings suggest that glucose-stimulated translation of proinsulin may require fully modified tRNA(Lys)(UUU), which could potentially explain the molecular pathogenesis of T2D in patients carrying cdkal1 risk alleles.

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  • Expression of a constitutively active calcineurin encoded by an intron-retaining mRNA in follicular keratinocytes. Reviewed International journal

    Atsushi Fujimura, Hiroyuki Michiue, Tei-ichi Nishiki, Iori Ohmori, Fan-Yan Wei, Hideki Matsui, Kazuhito Tomizawa

    PloS one   6 ( 3 )   e17685   2011.3

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    Hair growth is a highly regulated cyclical process. Immunosuppressive immunophilin ligands such as cyclosporin A (CsA) and FK506 are known as potent hair growth modulatory agents in rodents and humans that induce active hair growth and inhibit hair follicle regression. The immunosuppressive effectiveness of these drugs has been generally attributed to inhibition of T cell activation through well-characterized pathways. Specifically, CsA and FK506 bind to intracellular proteins, principally cyclophilin A and FKBP12, respectively, and thereby inhibit the phosphatase calcineurin (Cn). The calcineurin (Cn)/NFAT pathway has an important, but poorly understood, role in the regulation of hair follicle development. Here we show that a novel-splicing variant of calcineurin Aß CnAß-FK, which is encoded by an intron-retaining mRNA and is deficient in the autoinhibitory domain, is predominantly expressed in mature follicular keratinocytes but not in the proliferating keratinocytes of rodents. CnAß-FK was weakly sensitive to Ca(2+) and dephosphorylated NFATc2 under low Ca(2+) levels in keratinocytes. Inhibition of Cn/NFAT induced hair growth in nude mice. Cyclin G2 was identified as a novel target of the Cn/NFATc2 pathway and its expression in follicular keratinocytes was reduced by inhibition of Cn/NFAT. Overexpression of cyclin G2 arrested the cell cycle in follicular keratinocytes in vitro and the Cn inhibitor, cyclosporin A, inhibited nuclear localization of NFATc2, resulting in decreased cyclin G2 expression in follicular keratinocytes of rats in vivo. We therefore suggest that the calcineurin/NFAT pathway has a unique regulatory role in hair follicle development.

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  • Regulation of mitochondrial dynamics and neurodegenerative diseases. Reviewed

    Xiao-Jian Han, Kazuhito Tomizawa, Atsushi Fujimura, Iori Ohmori, Tei-Ichi Nishiki, Masayuki Matsushita, Hideki Matsui

    Acta medica Okayama   65 ( 1 )   1 - 10   2011.2

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    Mitochondria are important cellular organelles in most metabolic processes and have a highly dynamic nature, undergoing frequent fission and fusion. The dynamic balance between fission and fusion plays critical roles in mitochondrial functions. In recent studies, several large GTPases have been identified as key molecular factors in mitochondrial fission and fusion. Moreover, the posttranslational modifications of these large GTPases, including phosphorylation, ubiquitination and SUMOylation, have been shown to be involved in the regulation of mitochondrial dynamics. Neurons are particularly sensitive and vulnerable to any abnormalities in mitochondrial dynamics, due to their large energy demand and long extended processes. Emerging evidences have thus indicated a strong linkage between mitochondria and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and Huntington's disease. In this review, we will describe the regulation of mitochondrial dynamics and its role in neurodegenerative diseases.

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  • Poly-arginine domainによる細胞内導入効率と細胞制御について

    櫃田 隆, 道上 宏之, 山口 晃正, 藤村 篤史, 富澤 一仁, 松井 秀樹

    日本生理学雑誌   73 ( 2 )   36 - 36   2011.2

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  • Delivery of sodium borocaptate to glioma cells using immunoliposome conjugated with anti-EGFR antibodies by ZZ-His. Reviewed International journal

    Bin Feng, Kazuhito Tomizawa, Hiroyuki Michiue, Shin-ichi Miyatake, Xiao-Jian Han, Atsushi Fujimura, Masaharu Seno, Mitsunori Kirihata, Hideki Matsui

    Biomaterials   30 ( 9 )   1746 - 55   2009.3

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    Nanoparticles are effective of delivering cargo into cells. Here, sodium borocaptate (BSH) was encapsulated in liposomes composed of nickel lipid, and anti-epidermal growth factor receptor (EGFR) antibodies were conjugated to the liposomes using the antibody affinity motif of protein A (ZZ) as an adaptor (immunoliposomes). The immunoliposomes were used to deliver BSH into EGFR-overexpressing glioma cells. Immunohistochemical analysis using an anti-BSH monoclonal antibody revealed that BSH was delivered effectively into the cells but not into EGFR-deficient glioma or primary astrocytes. In an animal model of brain tumors, both the liposomes and the BSH were only observed in the tumor. Moreover, the efficiency of (10)B's delivery into glioma cells was confirmed by inductively coupled plasma-atomic emission spectrometry (ICP-AES) both in vitro and in vivo. The results suggest that this system utilizing immunoliposomes provides an effective means of delivering (10)B into glioma cells in boron neutron capture therapy (BNCT).

    DOI: 10.1016/j.biomaterials.2008.12.010

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  • A CONSTITUTIVELY ACTIVE CALCINEURIN ENCODED BY AN INTRON-RETAINING MESSENGER RNA IS REQUIRED FOR HAIR FOLLICLE DEVELOPMENT

    Atsushi Fujimura, Kazuhito Tomizawa, Hiroyuki Michiue, Tei-ichi Nishiki, Iori Ohmori, Hideki Matsui

    JOURNAL OF PHYSIOLOGICAL SCIENCES   59   244 - 244   2009

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  • DELIVERY OF SODIUM BOROCAPTATE TO GLIOMA CELLS USING IMMUNOLIPOSOME CONJUGATED WITH ANTI-EGFR ANTIBODIES BY ZZ-HIS

    Bin Feng, Kazuhito Tomizawa, Hiroyuki Michiue, Xiao-Jian Han, Atsushi Fujimura, Iori Ohmori, Tei-ichi Nishiki, Hideki Matsui

    JOURNAL OF PHYSIOLOGICAL SCIENCES   59   441 - 441   2009

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  • カルシニューリンAβの恒常的活性体は発毛メカニズムに関与する

    藤村 篤史, 富澤 一仁, 西本 禎一, 大守 伊織, 松井 秀樹

    日本生理学雑誌   70 ( 2 )   74 - 74   2008.2

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Books

  • THE ROLE OF EPIGENETIC MODIFICATIONS IN CANCER PROGRESSION

    Lei Chang, Hongquan Zhang, Atsushi Fujimura, Hanna Lucie Sladitschek, Hailong Pei( Role: Edit)

    Frontiers Media SA  2021.2 

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MISC

  • MPNSTの癌幹細胞性維持に対する腫瘍内のアドレナリン合成酵素の役割

    片山 晴喜, 藤村 篤史, 中田 英二, 大谷 悠介, 藤原 智洋, 国定 俊之, 神谷 厚範, 尾崎 敏文

    日本整形外科学会雑誌   96 ( 8 )   S1768 - S1768   2022.9

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  • 脳腫瘍と微小環境 分化型膠芽腫細胞はYAP/TAZ-TEAD-CCN1経路によってマクロファージ浸潤を促進し、間葉系微小環境を構築する

    畝田 篤仁, 黒住 和彦, 藤村 篤史, 藤井 謙太郎, 石田 穣治, 坪井 伸成, 牧野 圭悟, 平野 秀一郎, 神谷 厚範, 伊達 勲

    Brain Tumor Pathology   38 ( Suppl. )   054 - 054   2021.5

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  • Developing a tumor-selective boron agent for next generation BNCT

    藤村篤史, 藤村篤史, 井川和代, 植田愛, 渡辺香里, 道上宏之, 市川康明, 古矢修一

    月刊メディカル・サイエンス・ダイジェスト   46 ( 8 )   535 - 537   2020

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  • The role of differentiated glioblastoma cells through multicellular paracrine interactions in the tumor microenvironment

    畝田篤仁, 畝田篤仁, 黒住和彦, 黒住和彦, 藤村篤史, 藤井謙太郎, 石田穣治, 島津洋介, 大谷理浩, 冨田祐介, 服部靖彦, 松本悠司, 坪井伸成, 牧野圭悟, 平野秀一郎, 神谷厚範, 伊達勲

    日本脳腫瘍学会プログラム・抄録集   38th   2020

  • A phenotypic shift of glioblastoma cells via annexin A2-STAT3-oncostatin M receptor axis

    平野秀一郎, 松本悠司, 松本悠司, 市川智継, 市川智継, 黒住和彦, 黒住和彦, 大谷理浩, 大谷理浩, 藤村篤史, 藤井謙太郎, 島津洋介, 冨田祐介, 冨田祐介, 服部靖彦, 畝田篤仁, 坪井伸成, 牧野圭悟, 伊達勲

    日本脳腫瘍学会プログラム・抄録集   38th   2020

  • tRNA修飾酵素CDK5RAP1は膠芽腫幹細胞様細胞に重要である(Detoxification of N6-isopentenyladenosine by Cdk5rap1 controls the cell fate of glioma initiating cells)

    山本 隆広, 藤村 篤史, 魏 范研, 篠島 直樹, 黒田 順一郎, 武笠 晃丈, 富澤 一仁

    日本癌学会総会記事   78回   P - 3054   2019.9

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  • グリオーマにおけるannexin A2-STAT3-oncostatin M receptorを介したmesenchymal transition

    松本悠司, 市川智継, 市川智継, 黒住和彦, 大谷理浩, 大谷理浩, 藤村篤史, 藤井謙太郎, 冨田祐介, 服部靖彦, 畝田篤仁, 坪井伸成, 兼田圭介, 牧野圭悟, 伊達勲

    日本分子脳神経外科学会プログラム・抄録集   20th   2019

  • Annexin A2-STAT3-oncostatin M receptorが規定するグリオーマ表現型シフト

    松本悠司, 市川智継, 市川智継, 黒住和彦, 大谷理浩, 大谷理浩, 藤村篤史, 藤井謙太郎, 冨田祐介, 服部靖彦, 畝田篤仁, 兼田圭介, 牧野圭悟, 伊達勲

    日本脳腫瘍学会プログラム・抄録集   37th   2019

  • ミトコンドリアtRNA修飾酵素CDK5RAP1によるチオメチル化修飾は膠芽腫細胞に重要である

    山本隆広, 山本隆広, 藤村篤史, 魏范研, 甲斐恵太郎, 竹崎達也, 大田和貴, 黒田順一郎, 篠島直樹, 富澤一仁, 武笠晃丈

    日本脳腫瘍学会プログラム・抄録集   37th   2019

  • ミトコンドリアtRNA修飾酵素CDK5RAP1によるチオメチル化修飾は膠芽腫細胞に重要である

    山本隆広, 山本隆広, 藤村篤史, 魏范研, 甲斐恵太郎, 竹崎達也, 大田和貴, 黒田順一郎, 篠島直樹, 富澤一仁, 武笠晃丈

    日本脳腫瘍学会プログラム・抄録集   37th   2019

  • 転写共役因子YAP/TAZによるCCN1の発現誘導を介した悪性神経膠腫進展の分子メカニズム

    畝田篤仁, 畝田篤仁, 黒住和彦, 藤村篤史, 藤井謙太郎, 清水俊彦, 冨田祐介, 服部靖彦, 松本悠司, 坪井伸成, 神谷厚範, 伊達勲

    日本脳腫瘍学会プログラム・抄録集   36th   2018

  • Annexin A2が規定するグリオーマ表現型シフトの機序解明

    松本悠司, 市川智継, 市川智継, 黒住和彦, 大谷理浩, 大谷理浩, 藤村篤史, 坪井伸成, 畝田篤仁, 服部靖彦, 冨田祐介, 清水俊彦, 藤井謙太郎, 伊達勲

    日本分子脳神経外科学会プログラム・抄録集   19th   2018

  • 転写共役因子YAP/TAZによるCCN1発現誘導を介した悪性神経膠腫進展の分子メカニズム

    畝田篤仁, 畝田篤仁, 黒住和彦, 藤村篤史, 藤井謙太郎, 清水俊彦, 冨田祐介, 服部靖彦, 松本悠司, 坪井伸成, 伊達勲

    日本分子脳神経外科学会プログラム・抄録集   19th   2018

  • 研究医育成の現状と課題(Vol.6) 研究医育成プログラムはつぎのステージへ プログラム後に根付く研究マインド涵養の場

    藤村 篤史

    医学のあゆみ   261 ( 12 )   1194 - 1196   2017.6

  • Cyclin G2は低酸素に誘導される神経膠芽腫の局所浸潤を細胞骨格動態の調節を介して促進する(Cyclin G2 promotes hypoxia-driven local invasion of glioblastoma by orchestrating cytoskeletal dynamics)

    藤村 篤史

    岡山医学会雑誌   126 ( 2 )   185 - 185   2014.8

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  • Establishment of hair-growth promoting peptides : an example of Trans-Dermal Approach

    Fragrance journal   41 ( 11 )   23 - 27   2013.11

  • 研究志向学生の育成を目指して ARTプログラムによるシームレスな医学研究者育成システム

    松井 秀樹, 藤村 篤史

    日本生理学雑誌   74 ( 6 )   297 - 298   2012.11

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  • 毛包内ケラチノサイトにおけるイントロン含有mRNAによりコードされる恒常活性型カルシニューリンの発現(Expression of a constitutlvely active calcineurin encoded by an intron-retaining mRNA in follicular keratinocytes)

    藤村 篤史

    岡山医学会雑誌   124 ( 2 )   191 - 192   2012.8

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  • Barrett腺癌におけるHER2発現の検討

    田中 健大, 藤村 篤史

    日本消化器病学会雑誌   108 ( 臨増大会 )   A778 - A778   2011.9

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Industrial property rights

  • CANCER LESION TISSUE EVALUATION FOR OPTIMIZING EFFECT OF BORON NEUTRON CAPTURE THERAPY

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    Applicant:Okayama University

    Application no:PCT/JP2019/005727  Date applied:2019.2.8

    Announcement no:WO2019/160129 

    Publication no:WO2019-160129  Date published:2019822

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  • METHOD FOR GENERATING SOMATIC STEM CELLS

    Stefano Piccolo, Luca Azzolin, Tito Panciera, Michelangelo Cordenonsi, Francesca Zanconato, Atsushi Fujimura

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    Applicant:Padova University

    Application no:WO2015EP70305  Date applied:2015.9.4

    Announcement no:WO2017036565A1  Date announced:2017.3.9

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  • 発毛促進剤

    松井 秀樹, 富澤 一仁, 藤村 篤史

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    Applicant:国立大学法人 岡山大学

    Application no:PCT/JP2008/069004  Date applied:2008.10.21

    Announcement no:WO2009/054361A1 

    Publication no:WO2009-054361  Date published:2009430

    Patent/Registration no:特許第5399913号  Date registered:2013.11.1 

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Awards

  • Okayama University Young Top Researcher Award

    2021.2   Okayama University  

    Atsushi Fujimura

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  • 令和2年度 大藤内分泌医学賞

    2020.7   岡山大学病院  

    藤村篤史

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  • 平成25年度 岡山医学会賞 新見賞

    2014.3   岡山医学会  

    藤村篤史

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  • 平成24年度 岡山大学学会賞等受賞者

    2012.10   岡山大学  

    藤村篤史

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  • 平成23年度 岡山医学会賞 結城賞

    2012.3   岡山医学会  

    藤村篤史

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  • 第89回日本生理学会大会 ポスターアワード

    2012.3   日本生理学会  

    藤村篤史

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  • 第6回リバネス研究費 和光純薬賞

    2011.9   リバネス  

    藤村篤史

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  • 第101回日本内科学会中国支部 奨励賞

    2009.9   日本内科学会中国支部  

    藤村篤史

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Research Projects

  • 乳癌進展におけるメカノ応答性翻訳センサーの分子機構の解明と抗癌剤開発基盤の創成

    Grant number:23K06676  2023.04 - 2026.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    藤村 篤史, 増本 年男

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    Grant amount:\4680000 ( Direct expense: \3600000 、 Indirect expense:\1080000 )

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  • 癌幹細胞特異的翻訳機構に対する新規抗がん剤の探索

    Grant number:DNW-23032  2023.10 - 2025.09

    日本医療研究開発機構  創薬ブースター 

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  • 内在性カテコラミン合成経路を標的とした悪性末梢神経鞘腫瘍の新規治療方法の確立

    Grant number:23K08698  2023.04 - 2026.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    片山 晴喜, 中田 英二, 藤村 篤史, 尾崎 敏文

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    Grant amount:\4680000 ( Direct expense: \3600000 、 Indirect expense:\1080000 )

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  • 脂質代謝による翻訳制御を標的とした横紋筋肉腫の革新的治療法の開発

    Grant number:23K08678  2023.04 - 2026.03

    日本学術振興会  科学研究費助成事業  基盤研究(C)

    板野 拓人, 中田 英二, 藤村 篤史, 尾崎 敏文

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    Grant amount:\4550000 ( Direct expense: \3500000 、 Indirect expense:\1050000 )

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  • Creating new therapies for lung cancer by targeting de-differentiated Schwann cells in the cancer microenvironment.

    Grant number:22K09004  2022.04 - 2025.03

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

    大谷 悠介, 藤村 篤史, 豊岡 伸一

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

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  • 新規抗がん剤開発を目指すtRNA修飾酵素と阻害化合物の構造活性相関解明

    Grant number:22K05459  2022.04 - 2025.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    安藤 隆幸, 藤村 篤史, 石川 吉伸

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

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  • Development of anticancer drugs against cancer stem cell-specific translation machinery

    Grant number:DNW-22015  2022.04 - 2023.03

    AMED  創薬ブースター 

    藤村篤史

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  • 新規ホウ素製剤による同種造血幹細胞移植後の閉塞性細気管支炎治療の開発

    Grant number:21K07730  2021.04 - 2024.03

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

    西森 久和, 藤村 篤史, 前田 嘉信

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    Authorship:Coinvestigator(s) 

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

    同種造血幹細胞移植後の肺合併症として閉塞性細気管支炎が知られています。この合併症についてマウスモデルを用いて再現できることが報告されており、当研究室内でも安定して合併症を発症できる系として確立しています。本年度は、このマウスモデルの基礎的データを収集するために、移植後におけるケモカインの発現に関して、蛋白レベルのみならずmRNAレベルでも解析を実施しました。さらに、移植後肺合併症をきたすメカニズムとしての肺内への移植細胞の移行とその細胞の種類についても解析を実施しました。この肺合併症に対する、新しい治療法として、ホウ素中性子捕捉療法を本研究のテーマとしております。新規ホウ素製剤OKD-001は、岡山大学で開発されたペプチドA6K水溶液(スリー・ディー・マトリックス社)とホウ素薬剤BSH水溶剤の混合剤ですが、両剤を混合することによりナノ粒子様構造体が形成され、細胞内に取り込まれることを見出しております。今年度はこれを再確認し、OKD-001が実際に活性化リンパ球およびマクロファージに効率よく取り込まれることを証明するために、まず、マウスモデルにおいて、活性化リンパ球、およびマクロファージを採取して、in vitroでOKD-001を加える実験を施行すること、また細胞内のホウ素濃度の時間的推移はICP質量分析装置(ICP-MS)(岡山大学資源植物科学研究所内)にて測定し、細胞内の効率よくとりこまれるCD44発現および至適条件を明らかにすることを予定しておりましたが、コロナ禍の中で施設移動等によるコロナ感染のリスクを鑑みて、安全に移動などが可能と判断できるタイミングで施行することといたしました。

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  • 加齢が及ぼす癌微小環境としての修飾核酸モドミクスの変調

    2021.04 - 2022.03

    東北大学  令和3年度加齢研共同研究 

    藤村篤史, 魏范研

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  • 次世代抗がん剤の創成を目指したtRNAエピトランスクリプトーム阻害剤の開発

    2020.06 - 2023.03

    国立研究開発法人日本医療研究開発機構  次世代がん医療創生研究事業 

    藤村 篤史, 安藤 隆幸, 石川 吉伸, 富澤 一仁

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  • 膠芽腫幹細胞を標的としたtRNAメチル化酵素阻害剤による制がん戦略の構築

    Grant number:20K07618  2020.04 - 2023.03

    日本学術振興会  科学研究費助成事業 基盤研究(C)  基盤研究(C)

    藤村 篤史, 石川 吉伸, 黒住 和彦, 富澤 一仁, 安藤 隆幸, 増本 年男, 中村 仁, 魏 范研

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    Grant amount:\4290000 ( Direct expense: \3300000 、 Indirect expense:\990000 )

    我々はこれまでに、膠芽腫幹細胞の幹細胞性を維持するのに必要な標的酵素を同定しており、それらに対する阻害剤の初期ヒット化合物を得ている。この分子機構をさらに解明し、抗がん剤として臨床応用可能なレベルまで化合物を洗練させるため、令和2年度には次の項目に取り組んだ。(1)Target validationの実施、(2)de novo膠芽腫での抗がん作用の実証、(3)リード化合物の創製。(1)については、膠芽腫幹細胞株を用いたノックダウン実験によって、標的酵素が実際にがん幹細胞性(自己複製能、未分化維持能、等)を維持するために必要であることを確認した。(2)については、de novo膠芽腫で用いるための動物種(例えば、GFAP-creマウス)の個体数増加に取り組み、de novo発がんモデルマウスが作出可能であることを確認した。初期ヒット化合物に続く有望な類縁体が完成し次第、いつでも動物実験に取り組めるよう準備を整えた。(3)については、初期ヒット化合物の標的酵素に対する阻害活性を増強させるために、共同研究者とともにドラッグデザインおよびその評価に取り組んだ。その結果、いくつかの修飾基が活性を著しく減弱させたり、あるいは逆に一部の修飾基が阻害作用の維持に必要であったりといった情報を取ることに成功した。このステップを継続することで、標的酵素に対する阻害作用を増強させるために必要な構造活性相関のデータを取りに行くことを、令和3年度以降も継続する。以上、令和2年度に実施した内容を踏まえて、令和3年度以降に実施すべき内容を精査し、効率的に研究の全体計画を進めることができるよう、綿密な準備を整えた。

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  • tRNAエピトランスクリプトーム創薬で実現するがん幹細胞標的型抗がん剤の開発

    2018.11 - 2020.03

    国立研究開発法人日本医療研究開発機構  次世代がん医療創生研究事業 

    藤村 篤史, 安藤 隆幸, 魏 范研, 富澤 一仁, 井上 謙吾

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  • 膠芽腫におけるBNCTプレシジョン・メディシン化を実現する統合的分子基盤の創出

    2018.10 - 2021.03

    国立研究開発法人日本医療研究開発機構  革新的がん医療実用化研究事業 

    藤村 篤史, 道上 宏之, 井川 和代, 古矢 修一, 土田 一輝, 富澤 一仁, 魏 范研

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  • Development of anti-cancer strategy by targeting tRNA modification enzymes

    Grant number:18K15241  2018.04 - 2020.03

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Early-Career Scientists  Grant-in-Aid for Early-Career Scientists

    Fujimura Atsushi

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    Grant amount:\4160000 ( Direct expense: \3200000 、 Indirect expense:\960000 )

    In this study, I focused on the molecular mechanism of "cancer stem cell-related translational manner." I revealed that tRNA modification enzyme X was crucial to sustain the stemness of glioma-initiating cells. I found that enzyme Y, which has similar structure and function of enzyme X, was also important for various kind of cancers. Moreover, I also identified enzyme Z as the other type of tRNA modification enzyme that controlled stemness in carcinoma. These findings prompt me to develop the anti-cancer strategy, especially next-generation anti-cancer drugs, which can target the cancer stem cells.

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  • Development of anticancer drugs based on the knowledge of the roles of Ftsj1-mediated tRNA modification

    Grant number:16K18989  2016.04 - 2018.03

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

    Fujimura Atsushi

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    Grant amount:\4030000 ( Direct expense: \3100000 、 Indirect expense:\930000 )

    To elucidate the roles of translational machinery in cancer biology, I focused on tRNA-modification enzyme FTSJ1, and investigated how FTSJ1 determined the cancer cell fate. FTSJ1 is required to sustain the cancer stem cell-related traits: when FTSJ1 is down-regulated, the cancer cells lost the self-renewal capacity and tumor-forming capacity. As a functional target of FTSJ1, I identified Cyr61 and CTGF, both of which are essential to control cancer stem cell. These results indicate the possibilities of the development of FTSJ1 inhibitor as a groundbreaking anti-cancer drug.

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Class subject in charge

  • Introduction to Medical and Dental Sciences (2023academic year) Concentration  - その他

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  • Introduction to Medical and Dental Sciences (2022academic year) Concentration  - その他

  • Physiology (1) (2022academic year) special  - その他

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  • 医学研究インターンシップ (2021academic year) 特別

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  • Physiology (1) (2021academic year) special  - その他

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  • 研究方法論基礎 (2021academic year) 特別

  • Research Projects and Practicals: Cellular Physiology I (2021academic year) special  - その他

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  • Research Projects and Practicals: Cellular Physiology II (2021academic year) special  - その他

  • Lecture and Research Projects: Cellular Physiology II (2021academic year) special  - その他

  • Practice in Physiology (1) (2020academic year) special  - その他

  • Physiology (1) (2020academic year) special  - その他

  • Research Projects and Practicals: Cellular Physiology I (2020academic year) special  - その他

  • Lecture and Research Projects: Cellular Physiology I (2020academic year) special  - その他

  • Research Projects and Practicals: Cellular Physiology II (2020academic year) special  - その他

  • Lecture and Research Projects: Cellular Physiology II (2020academic year) special  - その他

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