Roles of endothelial-mesenchymal transition (EndoMT)-suppressing transcription factors in the inhibition of cancer progression

• Project/Area Number: 21K07094
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Niigata University
• Principal Investigator: Yoshimatsu Yasuhiro 新潟大学, 医歯学系, 准教授 (60586684)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: Etsファミリー転写因子 / 炎症性サイトカイン / レポーターマウス / がん関連線維芽細胞 / 内皮間葉移行 / 血管 / 間葉系細胞 / 血管内皮細胞 / 内皮特異的欠損 / TGF-β / Etsファミリー / EndoMT / リンパ管 / 脈管 / 内皮細胞 / がん

Outline of Research at the Start

血管内皮細胞を用いてあるEtsファミリー転写因子の機能を抑制するとがんの悪性化因子であるTGF-β2の発現が亢進した。この現象を動物個体レベルで検証するために血管内皮細胞で特異的に遺伝子を欠損させるシステムを用いて、Ets転写因子（仮称Ets A）の機能を抑制してTGF-β2産生量が増加するかについて検討する。また、TGF-β2産生量が増加していれば、血管の形態・機能について変化が見られる可能性が高いため、これについて観察および解析を行う。また同時にがんが起きている状況ではがんが悪性化する可能性が考えられるため、がんが悪性化するかについて検討する。

Outline of Final Research Achievements

Our group focused on the phenomenon of endothelial-mesenchymal transition, in which the properties of endothelial cells that compose the lumen of blood vessels and lymph vessels are drastically changed in inflammatory diseases including cancer, and identified factors that regulate this process in an attempt to elucidate the mechanism by which this phenomenon occurs. Since one of the Ets family transcription factors is involved in the suppression of inflammatory cytokine expression in blood vascular endothelial cells, mice lacking this gene were generated and showed abnormal vascular structures. Although its role in the malignant progression of cancer and inflammatory diseases remains to be elucidated, we were able to demonstrate and successfully establish the utility of reporter cells to analyze endothelial-mesenchymal transition.

Academic Significance and Societal Importance of the Research Achievements

EndoMT抑制因子としてのEtsファミリー転写因子の内皮細胞における役割については、血管及びリンパ管でそれぞれ異なる転写因子による、類似性があるものの複雑な転写制御ネットワークが存在することが示された。内皮間葉移行を経て産生される炎症性のサイトカインは周囲の細胞に影響を与えるため、本研究の成果や進行中の研究は関連疾患の悪性化の分子機序の解明の一部を担うと考えられる。EndoMTを解析するレポーター細胞についてはEndoMTに関する重要な分子が同定され、そのレポーターシステムの有用性が示されたため、今後もこの現象における分子機序の解明、ひいては関連疾患の発生機序の解明への寄与が期待される。

Research Products

• [Int'l Joint Research] Lund University(スウェーデン)
• [Journal Article] A MAP1B?cortactin?Tks5 axis regulates TNBC invasion and tumorigenesis (2024)
  • Author(s): Inoue Hiroki、Kanda Taku、Hayashi Gakuto、Munenaga Ryota、Yoshida Masayuki、Hasegawa Kana、Miyagawa Takuya、Kurumada Yukiya、Hasegawa Jumpei、Wada Tomoyuki、Horiuchi Motoi、Yoshimatsu Yasuhiro、Itoh Fumiko、Maemoto Yuki、Arasaki Kohei、Wakana Yuichi、Watabe Tetsuro、Matsushita Hiromichi、Harada Hironori、Tagaya Mitsuo
  • Journal Title: Journal of Cell Biology Volume: 223 Issue: 3 Pages: 1-19
  • DOI: 10.1083/jcb.202303102
  • Peer Reviewed / Open Access
• [Journal Article] Roles of TGF-β signals in tumor microenvironment via regulation of the formation and plasticity of vascular system (2023)
  • Author(s): Watabe T, Takahashi K, Pietras K, Yoshimatsu Y
  • Journal Title: Semin Cancer Biol. Volume: 92 Pages: 130-138
  • DOI: 10.1016/j.semcancer.2023.04.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] <scp>CD40</scp> is expressed in the subsets of endothelial cells undergoing partial endothelial?mesenchymal transition in tumor microenvironment (2023)
  • Author(s): Takahashi Kazuki、Kobayashi Miho、Katsumata Hisae、Tokizaki Shiori、Anzai Tatsuhiko、Ikeda Yukinori、Alcaide Daniel M.、Maeda Kentaro、Ishihara Makoto、Tahara Katsutoshi、Kubota Yoshiaki、Itoh Fumiko、Park Jihwan、Takahashi Kunihiko、Matsunaga Yukiko T.、Yoshimatsu Yasuhiro、Podyma‐Inoue Katarzyna A.、Watabe Tetsuro
  • Journal Title: Cancer Science Volume: 115 Issue: 2 Pages: 490-506
  • DOI: 10.1111/cas.16045
  • Peer Reviewed / Open Access
• [Journal Article] An analysis modality for vascular structures combining tissue-clearing technology and topological data analysis (2022)
  • Author(s): Takahashi K, Abe K, Kubota SI, Fukatsu N, Morishita Y, Yoshimatsu Y, Satoshi Hirakawa, Yoshiaki Kubota, Tetsuro Watabe, Shogo Ehata, Hiroki R. Ueda, Teppei Shimamura, Kohei Miyazono
  • Journal Title: Nature Communiactions Volume: 13 Issue: 1 Pages: 5239-5239
  • DOI: 10.1038/s41467-022-32848-2
  • Peer Reviewed / Open Access
• [Journal Article] Dose-response relationship of pulmonary disorders by inhalation exposure to cross-linked water-soluble acrylic acid polymers in F344 rats (2022)
  • Author(s): Takeda T, Yamano S, Goto Y, Hirai S, Furukawa Y, Kikuchi Y, Misumi K, Suzuki M, Takanobu K, Senoh H, Saito M, Kondo H, Daghlian G, Hong YK, Yoshimatsu Y, et al.
  • Journal Title: Particle Fibre and Toxicology Volume: 19 Issue: 1
  • DOI: 10.1186/s12989-022-00468-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 内皮細胞の機能低下がもたらす生体恒常性の破綻とその分子機序 (2022)
  • Author(s): 吉松康裕
  • Journal Title: 新潟医学会雑誌 Volume: 136 Pages: 69-74
• [Journal Article] Emerging roles of inflammation-mediated endothelial-mesenchymal transition in health and disease. (2022)
  • Author(s): Yoshimatsu Y, Watabe T.
  • Journal Title: Inflamm Regen Volume: 42 Issue: 1 Pages: 9-9
  • DOI: 10.1186/s41232-021-00186-3
  • Peer Reviewed / Open Access
• [Journal Article] Isolation and characterisation of lymphatic endothelial cells from lung tissues affected by lymphangioleiomyomatosis. (2021)
  • Author(s): Nishino K, Yoshimatsu Y, Muramatsu T, Sekimoto Y, Mitani K, Kobayashi E, Okamoto S, Ebana H, Okada Y, Kurihara M, Suzuki K, Inazawa J, Takahashi K, Watabe T, Seyama K.
  • Journal Title: Sci Rep Volume: 11 Issue: 1 Pages: 8406-8406
  • DOI: 10.1038/s41598-021-88064-3
  • Peer Reviewed / Open Access
• [Journal Article] ASK1 suppresses NK cell-mediated intravascular tumor cell clearance in lung metastasis. (2021)
  • Author(s): Fujimoto, M., Kamiyama, M., Fuse, K., Ryuno, H., Odawara, T., Furukawa, N., Yoshimatsu, Y., Watabe, T., Michaela, P.-M., Veronika, S., Tahara, H., Hayakawa, Y., Sato, T., Takeda, K., Naguro, I. and Ichijo, H.
  • Journal Title: Cancer Science Volume: 112 Issue: 4 Pages: 1633-1643
  • DOI: 10.1111/cas.14842
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Construction of transplantable artificial vascular tissue based on adipose tissue-derived mesenchymal stromal cells by a cell coating and cryopreservation technique (2021)
  • Author(s): Asano Y, Okano D, Matsusaki M, Watabe T, Yoshimatsu Y, Akashi M, Shimoda H
  • Journal Title: Scientific reports Volume: 11 Issue: 1 Pages: 17989-17989
  • DOI: 10.1038/s41598-021-97547-2
  • Peer Reviewed / Open Access
• [Presentation] リンパ管の内皮間葉移行においてTGF-βの下流経路で機能する転写因子の役割 (2023)
  • Author(s): Yasuhiro Yoshimatsu, Shiori Kimuro, Akihiko Inagawa, Masanori Hirashima, Tetsuro Watabe
  • Organizer: 第47回日本リンパ学会総会
• [Presentation] マウスモデルを用いた胎児項部浮腫とリンパ管形成異常に関わる新規原因遺伝子の探索 (2023)
  • Author(s): 杉山彰, Xinyi Liu, 椎谷友博, 吉松康裕, 平島正則
  • Organizer: 第47回日本リンパ学会総会
  • Invited
• [Presentation] 内皮間葉移行レポーター内皮細胞を用いたEndoMT遷移段階の可視化 (2023)
  • Author(s): 高橋和樹, 勝又寿枝, 小林美穂, 前田健太郎, 吉松康裕, 松永行子, 渡部徹郎
  • Organizer: 第47回日本リンパ学会総会
  • Int'l Joint Research
• [Presentation] TGF-βによる内皮間葉移行(EndoMT)の段階的遷移をEndoMTレポーター内皮細胞は可視化した (2023)
  • Author(s): 高橋 和樹, 勝又 寿枝, 小林 美穂, 時崎 詩織, 池田 行徳, 前田 健太郎, 井上 カタジナアンナ, 松永 行子, 吉松 康裕, 渡部 徹郎
  • Organizer: 第82回日本癌学会学術総会
• [Presentation] トリプルネガティブ乳がんにおける微小管結合タンパク質による浸潤突起形成制御 (2023)
  • Author(s): 井上弘樹, 吉田 正行, 吉松 康裕, 伊東 史子, 前本 佑樹, 新崎 恒平, 若菜 裕一 , 渡部 徹郎, 松下 弘通 , 原田 浩徳, 多賀谷 光男
  • Organizer: 第82回日本癌学会学術総会
• [Presentation] Endothelial-mesenchymal transition (EndoMT) reporter cells visualized multiple groups of cells during progression of TGF-β induced EndoMT (2023)
  • Author(s): Kazuki Takahashi, Miho Kobayashi, Hisae Katsumata, Yukinori Ikeda, Tatsuhiko Anzai, Katarzyna A. Podyma-Inoue, Daniel M Alcaide, Kentaro Maeda, Jihwan Park, Kunihiko Takahashi, Yukiko Matsunaga, Yasuhiro Yoshimatsu, Tetsuro Watabe
  • Organizer: Asia-Australia Vascular Biology Meeting 2023
  • Int'l Joint Research
• [Presentation] リンパ管・血管内皮細胞から線維芽細胞への分化を引き起こす分子メカニズム (2023)
  • Author(s): 吉松康裕
  • Organizer: 第46回日本分子生物学会年会
  • Invited
• [Presentation] 薬物を用いたリンパ管・血管吻合法の開発 (2023)
  • Author(s): 椎谷友博，Xinyi Liu，杉山 彰，吉松 康裕，平島 正則
  • Organizer: 第74回日本薬理学会北部会
• [Presentation] Platelet-derived growth factor receptor β expression is maintained by an Ets family transcription factor in lymphatic endothelium and is required for inflammatory lymphangiogenesis (2022)
  • Author(s): Yoshimatsu Y, Shiori Kimuro, Itoh Taichi, Akihiko Inagawa, Masanori Hirashima, Kohei Miyazono, Tetsuro Watabe
  • Organizer: The 81th Annual Meeting of the Japanese Cancer Association
  • Int'l Joint Research
• [Presentation] 脈管の恒常性維持と加齢との関係 (2022)
  • Author(s): 小林美穂, 高橋和樹, 勝又寿枝, 廣瀬穂香, 吉松康裕, 渡部徹郎
  • Organizer: 第45回日本分子生物学会年会
  • Invited
• [Presentation] 内皮間葉移行（EndoMT）レポーター内皮細胞を用いたEndoMT遷移段階の検出 (2022)
  • Author(s): 勝又寿枝,高橋和樹,小林美穂,前田健太郎,吉松康裕,松永行子,渡部徹郎
  • Organizer: 第45回日本分子生物学会年会
• [Presentation] Roles of an Ets family transcription factor in platelet-derived growth factor -mediated lymphangiogenesis (2022)
  • Author(s): Yasuhiro Yoshimatsu, Shiori Kimuro,Taich Itoh, Akihiko Inagawa, Masanori Hirashima, Kohei Miyazono, Tetsuro Watabe
  • Organizer: The 30th Annual Meeting of the Japanese Vascular Biology and Medicine Organization
• [Presentation] Roles of an Ets family transcription factor in platelet-derived growth factor signal-mediated lymphangiogenesis (2022)
  • Author(s): Yasuhiro Yoshimatsu, Shiori Kimuro,Taich Itoh, Akihiko Inagawa, Masanori Hirashima, Kohei Miyazono, Tetsuro Watabe
  • Organizer: The 46th Meeting of the Japanese Society of Lymphology
  • Invited
• [Presentation] Activation of epithelial-mesenchymal transition program in oral cancer cells under TGF-β-induced cell cycle arrest (2021)
  • Author(s): Katarzyna A. Inoue, Kazuki Takahashi, Sakakitani Shintaro, Daizo Koinuma, Akinari Sugauchi, Maki Saito, Atsushi Kaida, Yasuhiro Yoshimatsu, Toshihiro Uchihashi, Masahiko Miura, Kohei Miyazono, Tetsuro Watabe.
  • Organizer: TGF-β Superfamily Conference: Signaling in Development and Disease (FASEB)
  • Int'l Joint Research
• [Presentation] Role of an ETS family transcription factor in endothelial-mesenchymal transition (EndoMT)-driven EMT (2021)
  • Author(s): Yasuhiro Yoshimatsu, Kentaro Maeda, Naoya Takahashi, Ikumi Wakabayashi, Shiori Kimuro, Kazuki Takahashi, Miho Kobayashi, Katarzyna A. Podyma-Inoue, Masanori Hirashima, Kohei Miyazono, Tetsuro Watabe
  • Organizer: The 80th Annual Meeting of the Japanese Cancer Association
• [Presentation] Oral cancer cells under TGF-β-induced cell cycle arrest exhibit motile phenotypes through induction of epithelial-mesenchymal transition (EMT) (2021)
  • Author(s): Kazuki Takahashi, Katarzyna A. Inoue, Sakakitani Shintaro, Toru Konisi, Akinari Sugauchi, Maki Saito, Atsushi Kaida, Daizo Koinuma, Yasuhiro Yoshimatsu, Toshihiro Uchihashi, Mikihiko Kogo, Masahiko Miura, Kohei Miyazono, Tetsuro Watabe
  • Organizer: The 80th Annual Meeting of the Japanese Cancer Association
• [Presentation] リンパ管内皮細胞における内皮間葉移行はEtsファミリー転写因子の発現低下を介したActivin シグナルの活性化により亢進する (2021)
  • Author(s): 吉松康裕, 紀室志織, 稲川諒彦, 前田健太郎, 平島正則, 渡部徹郎.
  • Organizer: 第 29 回日本血管生物医学会
• [Presentation] 内皮細胞の機能低下がもたらす生体恒常性の破綻とその分子機序 (2021)
  • Author(s): 吉松康裕
  • Organizer: 第759回新潟医学会
  • Invited
• [Book] 化学と生物 (2022)
  • Author(s): 吉松 康裕
  • Total Pages: 3
  • Publisher: 国際文献社