Roles of transcription factors role of transcription factors in the maintenance of endothelial identity

• Project/Area Number: 17K07157
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Niigata University (2019-2020); Tokyo Medical and Dental University (2017-2018)
• Principal Investigator: Yoshimatsu Yasuhiro 新潟大学, 医歯学系, 准教授 (60586684)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: がん関連線維芽細胞 / 血管 / 血管内皮細胞 / 間葉系細胞 / 内皮間葉移行 / TGF-β / Activin / Etsファミリー転写因子 / 炎症性サイトカイン / がん悪性化 / EndMT / Ets family 転写因子 / リンパ管内皮細胞 / 内皮細胞 / 内皮間葉移行（EndMT） / 転写因子 / 発現制御

Outline of Final Research Achievements

A subset of fibroblasts, which are involved in the malignant progression of various diseases, differentiate from endothelial cells through a phenomenon called endothelial-mesenchymal transition. However, the role and molecular mechanism of the endothelial differentiation remain unclear. Therefore, we attempted to elucidate it in this study. Hypothesizing that transcription factors are necessary for endothelial cells to maintain their properties as endothelial cells without undergoing endothelial-mesenchymal transition, we identified an Ets family transcription factor that functions in blood vascular endothelial cells. We also found that a different Ets family transcription factor is important in lymphatic endothelial cells, which are a different type of endothelial cells. In addition, we were able to identify different endogenous cytokines as accelerators of endothelial-mesenchymal transition that are regulated by these transcription factors, respectively.

Academic Significance and Societal Importance of the Research Achievements

今回解明されたEndMT抑制因子としてのEtsファミリー転写因子の役割から、内皮細胞から線維芽細胞へと分化する際には、Etsファミリーを含む複数の転写因子によってそれぞれの細胞マーカーの発現が制御を受けることが明らかになり、複雑な転写ネットワークが存在することが示唆された。腫瘍血管内皮細胞やがん関連線維芽細胞は特に正常のそれとは非常に異なる性質を持つことが知られており、腫瘍における特異な生命現象の理解に大きく貢献したと考えられる。さらに今回このEndMTに関与することが示された分子群は、がんにおける新たな標的分子や診断マーカーになる可能性があり、がんの分子標的治療の選択肢を広げた意義は大きい。

Research Products

• [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] Roles of Transcription Factors and Signaling Networks in the Regulation of Lymphatic Endothelial Cell Function (2020)
  • Author(s): 吉松 康裕, 渡部 徹郎
  • Journal Title: The Journal of Japanese College of Angiology Volume: 60 Issue: 11 Pages: 193-196
  • DOI: 10.7133/jca.20-00032
  • NAID: 130007937886
  • ISSN: 0387-1126, 1880-8840
  • Year and Date: 2020-11-10
  • Peer Reviewed / Open Access
• [Journal Article] TGF-β and TNF-α cooperatively induce mesenchymal transition of lymphatic endothelial cells via activation of Activin signals (2020)
  • Author(s): Yoshimatsu Y, Kimuro S, Pauty J, Takagaki K, Nomiyama S, Inagawa A, Maeda K, Podyma-InoueKA, Kajiya K, Matsunaga Y, Watabe T
  • Journal Title: PLOS ONE Volume: 15 Issue: 5 Pages: e0232356-e0232356
  • DOI: 10.1371/journal.pone.0232356
  • Peer Reviewed / Open Access
• [Journal Article] Peptide-2 from mouse myostatin precursor protein alleviates muscle wasting in cancer-associated cachexia (2020)
  • Author(s): Chiharu Ojima, Yuri Noguchi, Tatsuki Miyamoto, Yuki Saito, Hiroki Orihashi, Yasuhiro Yoshimatsu, Tetsuro Watabe, Kentaro Takayama, Yoshio Hayashi, Fumiko Itoh.
  • Journal Title: Cancer Sci Volume: 111 Issue: 8 Pages: 2954-2964
  • DOI: 10.1111/cas.14520
  • Peer Reviewed / Open Access
• [Journal Article] TNF-α enhances TGF-β-induced endothelial-to-mesenchymal transition via TGF-β signal augmentation (2020)
  • Author(s): Yasuhiro Yoshimatsu, Ikumi Wakabayashi, Shiori Kimuro, Naoya Takahashi, Kazuki Takahashi, Miho Kobayashi, Nako Maishi, Katarzyna A. Podyma-Inoue, Kyoko Hida, Kohei Miyazono, Tetsuro Watabe
  • Journal Title: Cancer Sciense Volume: - Issue: 7 Pages: 2385-2399
  • DOI: 10.1111/cas.14455
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Targeting all transforming growth factor-β isoforms with an Fc chimeric receptor impairs tumor growth and angiogenesis of oral squamous cell cancer (2020)
  • Author(s): Takahashi Kazuki, Akatsu Yuichi, Podyma-Inoue Katarzyna A., Matsumoto Takehisa, Takahashi Hitomi, Yoshimatsu Yasuhiro, Koinuma Daizo, Shirouzu Mikako, Miyazono Kohei, Watabe Tetsuro
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 36 Pages: 12559-12572
  • DOI: 10.1074/jbc.ra120.012492
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fibroblast growth factor signals regulate transforming growth factor-β-induced endothelial-to-myofibroblast transition of tumor endothelial cells via Elk1 (2019)
  • Author(s): Akatsu Y*, Takahashi N*, Yoshimatsu Y*, Kimuro S, Muramatsu T, Katsura A, Maishi N, Suzuki HI, Inazawa J, Hida K, Miyazono K, Watabe T. (＊equal contribution)
  • Journal Title: Molecular Oncology Volume: 13 Issue: 8 Pages: 1706-1724
  • DOI: 10.1002/1878-0261.12504
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin-13 receptor α2 is a novel marker and potential therapeutic target for human melanoma. (2019)
  • Author(s): Okamoto H*, Yoshimatsu Y*, Tomizawa T*, Kunita A*, Takayama R*, Morikawa T, Komura D, Takahashi K, Oshima T, Sato M, Komai M, Podyma-Inoue KA, Uchida H, Hamada H, Fujiu K, Ishikawa S, Fukayama M, Fukuhara T, Watabe T. (* equal contributor)
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 1281-1281
  • DOI: 10.1038/s41598-019-39018-3
  • Peer Reviewed / Open Access
• [Journal Article] Regulatory role of transforming growth factor-β signals in the migration and tumor formation of HOC313-LM cells, an oral squamous cell carcinoma. (2018)
  • Author(s): Takahashi K, Podyma-Inoue KA, Takao C, Yoshimatsu Y, Muramatsu T, Inazawa J, Watabe T.
  • Journal Title: The Journal of the Stomatological Society Volume: 85 Pages: 52-61
  • NAID: 40021649452
  • Peer Reviewed
• [Journal Article] リンパ管の成熟過程を制御する新規リモデリング因子 (2018)
  • Author(s): 諸岡七美, 吉松康裕
  • Journal Title: 細胞 Volume: 50 Pages: 678-681
• [Journal Article] リンパ管形成における血小板由来増殖因子シグナルの役割とその分子メカニズム (2017)
  • Author(s): 吉松康裕，宮崎秀幹，山崎智子，三嶋弘一，赤津裕一，伊藤太智，稲川諒彦，宮園浩平, 渡部徹郎
  • Journal Title: リンパ学 Japanese journal of lymphology Volume: 40-2 Pages: 94-98
  • Open Access
• [Presentation] 血管・リンパ管内皮細胞の恒常性維持機構におけるtransforming growth factor-βスーパーファミリーの役割 (2020)
  • Author(s): 吉松康裕
  • Organizer: 第19回日本本再生医療学会総会
  • Invited
• [Presentation] リンパ管内皮細胞の恒常性維持機構におけるtransforming growth factor-βスーパーファミリーの役割 (2020)
  • Author(s): 吉松康裕
  • Organizer: 第41回日本炎症・再生医学会
  • Invited
• [Presentation] 内皮細胞の恒常性維持機構におけるtransforming growth factor-βスーパーファミリーの役割 (2020)
  • Author(s): 吉松康裕，宮園浩平，渡部徹郎
  • Organizer: 第44回日本リンパ学会総会
  • Invited
• [Presentation] リンパ脈管筋腫症肺組織からのリンパ管内皮細胞の分離および特性分析 (2020)
  • Author(s): 西野宏一, 吉松康裕, 関本康人, 岡本翔一, 村松智輝, 三谷恵子, 小林悦子, 江花弘基, 栗原正利,稲澤譲治, 高橋和久, 渡部徹郎, 瀬山邦明
  • Organizer: 第44回日本リンパ学会総会
  • Invited
• [Presentation] Endothelial-Derived Transforming Growth Factor-β/Activin Signals Activated by Inflammation-Related Cytokines During Endothelial-to-Mesenchymal Transition Induce Epithelial-to-Mesenchymal Transition (2020)
  • Author(s): Yasuhiro Yoshimatsu, Ikumi Wakabayashi, Shiori Kimuro, Naoya Takahashi, Kazuki Takahashi, Miho Kobayashi, Katarzyna A. Podyma-Inoue, Kohei Miyazono, Tetsuro Watabe.
  • Organizer: The 21st International Vascular Biology Meeting
  • Int'l Joint Research
• [Presentation] TNF-αはTGF-βシグナルの増強を介してTGF-βによって 誘導される血管の内皮間葉移行を促進する (2020)
  • Author(s): 若林育海,吉松康裕,紀室志織,高橋直也,高橋和樹,伊東史子,小林美穂,井上カタジナアンナ,宮園浩平,渡部徹郎
  • Organizer: 第93回日本生化学会大会
  • Invited
• [Presentation] 血管・リンパ管内皮細胞の恒常性維持機構におけるtransforming growth factor-βスーパーファミリーの役割 (2020)
  • Author(s): 吉松康裕，宮園浩平，渡部徹郎
  • Organizer: 第93回日本生化学会大会
  • Invited
• [Presentation] Oral squamous carcinoma cells under TGF-β-induced cell cycle arrest represent highly motile and invasive population (2020)
  • Author(s): Katarzyna A. Inoue, Kazuki Takahashi, Maki Saito, Atsushi Kaida, Akinari Sugauchi, Toshihiro Uchihashi, Yasuhiro Yoshimatsu, Susumu Tanaka, Masahiko Miura, Mikihiko Kogo, Tetsuro Watabe.
  • Organizer: AACR Virtual Special Conference
  • Int'l Joint Research
• [Presentation] Endothelial-derived TGF-β signals activated during endothelial-to-mesenchymal transition induce EMT of oral cancer cells. (2020)
  • Author(s): Yasuhiro Yoshimatsu, Ikumi Wakabayashi, Shiori Kimuro, Naoya Takahashi, Kazuki Takahashi, Miho Kobayashi, Katarzyna A. Podyma-Inoue, Kohei Miyazono, Tetsuro Watabe.
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] TGF-β-induced cell cycle arrest is associated with increased migration and metastasis of oral squamous carcinoma cells. (2020)
  • Author(s): Kazuki Takahashi, Katarzyna A. Inoue, Atsushi Kaida, Akinari Sugauchi, Toshihiro Uchihashi, Yasuhiro Yoshimatsu, Susumu Tanaka, Masahiko Miura, Mikihiko Kogo, Tetsuro Watabe.
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Regulatory mechanism of endothelium-derived TGF-β/Activin signals activated during endothelial-mesenchymal transition. (2020)
  • Author(s): Yasuhiro Yoshimatsu, Kohei Miyazono, Tetsuro Watabe.
  • Organizer: 第42回日本分子生物学会年会
  • Invited
• [Presentation] 見えてきたリンパ管の新たな役割と関連疾患 (2020)
  • Author(s): 吉松康裕
  • Organizer: 第42回日本分子生物学会年会 フォーラム「管学」
  • Invited
• [Presentation] 線維芽細胞増殖因子(FGF2)は腫瘍血管内皮細胞においてTGF-βによって誘導される内皮-筋線維芽移行を制御する (2019)
  • Author(s): 吉松康裕、赤津裕一、 高橋直也、紀室志織、村松智輝、桂彰宏、間石奈湖、 鈴木洋、稲澤譲治、樋田京子、宮園浩平、渡部徹郎.
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] リンパ管内皮細胞の機能制御における転写因子・シグナルネットワークの役割 (2019)
  • Author(s): 吉松康裕
  • Organizer: 第60回日本脈管学会総会
  • Invited
• [Presentation] Transforming growth factor-βおよびtumor necrosis factor-αはActivinシグナルの活性化を介してリンパ管内皮細胞における内皮間葉移行を亢進する (2019)
  • Author(s): 紀室志織、吉松康裕、稲川諒彦、前田健太郎、渡部徹郎.
  • Organizer: 第27回日本血管生物医学会学術集会
• [Presentation] 悪性黒色腫の進展におけるIL13Rα2の機能解析 (2019)
  • Author(s): 高山莉那、岡本勇人、吉松康裕、富澤泰志、国田朱子、高橋和樹、 井上カタジナアンナ、深山正久、 福原武志 、渡部徹郎.
  • Organizer: 第27回日本血管生物医学会学術集会
• [Presentation] リンパ管内皮細胞における内皮間葉移行の分子メカニズム (2019)
  • Author(s): 吉松康裕, 稲川諒彦, 紀室志織, 前田健太郎, 渡部徹郎.
  • Organizer: 第43回日本リンパ学会総会
• [Presentation] リンパ管内皮細胞における内皮間葉移行（EndMT）の分子機序 (2018)
  • Author(s): 吉松康裕
  • Organizer: 第83回日本口腔病学会学術大会
  • Invited
• [Presentation] リンパ管の形成過程や恒常性維持における転写因子・シグナル経路 (2018)
  • Author(s): 吉松康裕
  • Organizer: 第41回日本分子生物学会年会
  • Invited
• [Presentation] 口腔扁平上皮がん細胞のTGF-βによる悪性化と細胞周期制御の関連性の検討 (2018)
  • Author(s): 高橋和樹, 井上カタジナアンナ, 吉松康裕, 戒田篤志, 三浦雅彦, 渡部徹郎.
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] リンパ管内皮細胞における転写因子・ シグナルネットワークの役割 (2018)
  • Author(s): 吉松康裕
  • Organizer: 第42回日本リンパ学会総会
• [Presentation] BMP-9-ALK1 signal enhances TGF-β-induced endothelial-to-mesenchymal transition (2018)
  • Author(s): Yasuhiro Yoshimatsu, Taishi Tomizawa, Tetsuro Watabe.
  • Organizer: 12th International BMP Conference 2018
• [Presentation] Molecular mechanism of transforming growth factor β- induced endothelial-to-mesenchymal transition in lymphatic endothelial cells (2018)
  • Author(s): Yasuhiro Yoshimatsu, Akihiko Inawaga, Shiori Kimuro, Tetsuro Watabe.
  • Organizer: The 16th Korea-Japan Joint Symposium on Vascular Biology
• [Presentation] Tumor necrosis factor-α enhances transforming growth factor-β-induced endothelial mesenchymal transition in endothelial cells by augmenting both TNF-α and TGF-β signals reciprocally (2018)
  • Author(s): Yasuhiro Yoshimatsu, Naoya Takahashi, Kentaro Maeda, Kazuki Yoneyama, Kohei Miyazono, Tetsuro Watabe.
  • Organizer: International Vascular Biology Meeting 2018
• [Presentation] リンパ管形成や恒常性維持における転写因子・シグナルネットワークの役割 (2018)
  • Author(s): 吉松康裕、稲川諒彦、宮崎秀幹、山崎智子、赤津裕一、三嶋弘一、伊藤太智、宮園浩平、渡部徹郎
  • Organizer: 第123回日本解剖学会総会
  • Invited
• [Presentation] Tumor necrosis factor-αはtransforming growth factor-βにより誘導されるリンパ管内皮細胞の内皮間葉移行を亢進する (2017)
  • Author(s): 稲川諒彦, 吉松康裕, 前田健太郎, 渡部徹郎
  • Organizer: 第25回日本血管生物医学会学術集会
• [Presentation] もうひとつの脈管「リンパ管」 (2017)
  • Author(s): 吉松康裕
  • Organizer: 第90回日本生化学会大会（Conbio2017フォーラム ネオ血管学・新血管時代の幕開け）
• [Presentation] リンパ管形成を制御するシグナル・転写因子 (2017)
  • Author(s): 吉松康裕
  • Organizer: 第90回日本生化学会大会
  • Invited
• [Presentation] Exosomes secreted by oral squamous carcinoma cells undergoing TGF-β-induced epithelial to mesenchymal transition (2017)
  • Author(s): Katarzyna A. Inoue, Kazuki Takahashi, Takumi Matsuda, Yasuhiro Yoshimatsu, Miki Yokoyama, Tetsuro Watabe
  • Organizer: 第90回日本生化学会大会
• [Presentation] Cell cycle arrest in oral squamous carcinoma cells undergoing TGF-β-induced epithelial to mesenchymal transition (2017)
  • Author(s): Kazuki Takahashi, Katarzyna A. Inoue, Yasuhiro Yoshimatsu, Atsushi Kaida, Masahiko Miura, Tetsuro Watabe
  • Organizer: 第90回日本生化学会大会
• [Presentation] Relationship between cell cycle arrest and epithelial to mesenchymal transition (EMT) induced by TGF-β in oral squamous carcinoma cell (2017)
  • Author(s): Tetsuro Watabe, Kazuki Takahashi, Takumi Matsuda, Yasuhiro Yoshimatsu, Atsushi Kaida, Masahiko Miura and Katarzyna A. Inoue
  • Organizer: ERATO/AMED-CREST/PRESTO Joint International Symposium
  • Int'l Joint Research
• [Presentation] Cell cycle arrest in oral squamous carcinoma cells undergoing TGF-β-induced epithelial to mesenchymal transition (2017)
  • Author(s): Kazuki Takahashi, Katarzyna A. Inoue, Yasuhiro, Yoshimatsu, Atsushi Kaida, Masahiko Miura, Tetsuro Watabe
  • Organizer: Platform of Advanced Animal Model Support, FY2017 Technical Training Course for the youth
• [Presentation] Roles of signaling and transcriptional networks in the formation and maintenance of Blood and lymphatic vessels (2017)
  • Author(s): Yasuhiro Yoshimatsu
  • Organizer: The 15th Japan-Korea Joint Symposium of Vascular Biology
  • Int'l Joint Research / Invited
• [Presentation] 内皮細胞の恒常性維持におけるシグナル・転写ネットワークの役割 (2017)
  • Author(s): Yasuhiro Yoshimatsu
  • Organizer: 第５回リンパ学に関する松本カンファレンス
• [Presentation] Cell cycle arrest in oral squamous carcinoma cells undergoing TGF-β-induced epithelial to mesenchymal transition (2017)
  • Author(s): Katarzyna A. Inoue, Kazuki Takahashi, Takumi Matsuda, Yasuhiro Yoshimatsu, Atsushi Kaida, Masahiko Miura, Tetsuro Watabe
  • Organizer: FASEB Conference "TGF-B Superfamily: Signaling in Development and Disease"
  • Int'l Joint Research
• [Presentation] ELK3 is a functional regulator of Prox1 in lymphatic endothelial cells (2017)
  • Author(s): Yasuhiro Yoshimatsu, Taichi Itoh, Akihiko Inagawa, Kohei Miyazono, Tetsuro Watabe
  • Organizer: Lymphatic Forum 2017
  • Int'l Joint Research
• [Presentation] リンパ管形成における血小板由来増殖因子シグナルの役割とその分子メカニズム (2017)
  • Author(s): 吉松康裕
  • Organizer: 第41回日本リンパ学会総会
• [Book] リンパ学 第42巻，1号 「リンパ管内皮細胞における転写因子・シグナルネットワークの役割」 (2019)
  • Author(s): 吉松康裕, 山崎智子, 赤津裕一, 原田香織, 三嶋弘一, 宮崎秀幹, 伊藤太智, 稲川諒彦, 紀室志織, 宮園浩平, 渡部徹郎.
  • Total Pages: 4
  • Publisher: ライフメディコム
• [Book] 医学のあゆみ 第270巻，1号 「内皮間葉移行におけるTGF-βシグナルの役割」 (2019)
  • Author(s): 吉松康裕, 渡部徹郎
  • Total Pages: 7
  • Publisher: 医歯薬出版
• [Remarks] がんを進展させるがん関連線維芽細胞の血管内皮細胞からの形成を抑制するしくみを解明
  • URL: https://www.amed.go.jp/news/release_20190703-02.html
• [Remarks] 研究情報データベース 吉松康裕
  • URL: http://reins.tmd.ac.jp/html/100023022_ja.html#item_univ_gr_2
• [Patent(Industrial Property Rights)] 老化抑制剤 (2018)
  • Inventor(s): 渡部徹郎、吉松康裕、加治屋健太朗
  • Industrial Property Rights Holder: 渡部徹郎、吉松康裕、加治屋健太朗
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
• [Patent(Industrial Property Rights)] 老化抑制剤のスクリーニング方法 (2018)
  • Inventor(s): 渡部徹郎、吉松康裕、加治屋健太朗、高垣知輝
  • Industrial Property Rights Holder: 渡部徹郎、吉松康裕、加治屋健太朗、高垣知輝
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018