Elucidation of the molecular mechanism of cancer-related fibroblast induction and regulation of the tumor microenvironment based on its inhibition

• Project/Area Number: 20H00518
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: Fujita Health University (2022); Keio University (2020-2021)
• Principal Investigator: Saya Hideyuki 藤田医科大学, がん医療研究センター, センター長 (80264282)
• Co-Investigator(Kenkyū-buntansha): 信末 博行 藤田医科大学, がん医療研究センター, 講師 (90525685)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥45,630,000 (Direct Cost: ¥35,100,000、Indirect Cost: ¥10,530,000); Fiscal Year 2022: ¥13,130,000 (Direct Cost: ¥10,100,000、Indirect Cost: ¥3,030,000); Fiscal Year 2021: ¥13,130,000 (Direct Cost: ¥10,100,000、Indirect Cost: ¥3,030,000); Fiscal Year 2020: ¥19,370,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥4,470,000)
• Keywords: 腫瘍関連線維芽細胞 / アクチン / がん関連線維芽細胞 / 腫瘍微小環境 / MKL1 / がん微小環境 / 癌関連線維芽細胞 / アクチン細胞骨格 / 脂肪細胞

Outline of Research at the Start

脂肪細胞などがん組織中に存在する種々の間質細胞は、サイトカイン等の刺激によって活性化し、腫瘍の生育を支援する癌関連線維芽細胞（cancer-associated fibroblast: CAF）へと分化する。本研究は、がん細胞が脂肪細胞などの間質細胞をCAFへと転換する分子機構を解明し、そのプロセスを制御する因子を同定するとともに、その知見に基づいて、間質細胞からCAFへの分化を阻害することで腫瘍抑制するという新たな治療法の開発を目指す。

Outline of Final Research Achievements

Tumor microenvironment is composed of various cell types, of which cancer-associated fibroblasts (CAFs) are the major component. CAFs originate from resident fibroblasts, mesenchymal stem cells, epithelial cells and adipocytes, influence tumor growth by secreting inflammatory cytokines and growth factors. However, the molecular mechanism of which regulate the conversion from stromal cells into CAFs remains unclear. In this study, we found that soluble factors secreted from malignant osteosarcoma cells enhanced F-actin polymerization and the transcriptional activity by MKL1 in adipocytes, induced the dedifferentiation and further the conversion of these cells into CAF-like cells. These findings suggest that MKL1 acts as a master regulator of the conversion of stromal cells.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、アクチン動態により制御されるMKL1が間質細胞からCAFへの分化を誘導するマスタレギュレーターとして働くことを明らかにするとともに、標的としてアクチン細胞骨格という物理的要素の動態を変化させることで、間質細胞からCAFへの分化を阻害し微小環境制御により腫瘍抑制するという先駆的治療法の開発の可能性を見出しており、学術的に新しい概念を生み出すだけでなく、社会的意義も極めて大きい。

Research Products

• [Journal Article] Stromal reprogramming through dual PDGFRα/β blockade boosts the efficacy of anti-PD-1 immunotherapy in fibrotic tumors. (2022)
  • Author(s): T. Akiyama, T. Yasuda, T. Uchihara, N. Yasuda-Yoshihara, BJY. Tan, A. Yonemura, T. Semba, J. Yamasaki, Y. Komohara, K. Ohnishi, F. Wei, L. Fu, J. Zhang, F. Kitamura, K. Yamashita, K. Eto, S. Iwagami, H. Tsukamoto, T. Umemoto, M. Masuda, O. Nagano, Y. Satou, H. Saya, P. Tan, H. Baba, T. Ishimoto
  • Journal Title: Cancer Res. Volume: 83 Issue: 5 Pages: 753-770
  • DOI: 10.1158/0008-5472.can-22-1890
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Depletion of R270C Mutant p53 in Osteosarcoma Attenuates Cell Growth but Does Not Prevent Invasion and Metastasis In Vivo (2022)
  • Author(s): Shimizu Takatsune、Sugihara Eiji、Takeshima Hideyuki、Nobusue Hiroyuki、Yamaguchi Rui、Yamaguchi-Iwai Sayaka、Fukuchi Yumi、Ushijima Toshikazu、Muto Akihiro、Saya Hideyuki
  • Journal Title: Cells Volume: 11 Issue: 22 Pages: 3614-3614
  • DOI: 10.3390/cells11223614
  • Peer Reviewed / Open Access
• [Journal Article] Pigment epithelium-derived factor promotes peritoneal dissemination of ovarian cancer through induction of immunosuppressive macrophages (2022)
  • Author(s): Ueno Sayaka、Sudo Tamotsu、Saya Hideyuki、Sugihara Eiji
  • Journal Title: Communications Biology Volume: 5 Issue: 1 Pages: 904-919
  • DOI: 10.1038/s42003-022-03837-4
  • Peer Reviewed / Open Access
• [Journal Article] Interleukin-6-derived cancer-associated fibroblasts activate STAT3 pathway contributing to gemcitabine resistance in cholangiocarcinoma (2022)
  • Author(s): Kittirat Yingpinyapat、Suksawat Manida、Thongchot Suyanee、Padthaisong Sureerat、Phetcharaburanin Jutarop、Wangwiwatsin Arporn、Klanrit Poramate、Sangkhamanon Sakkarn、Titapun Attapol、Loilome Watcharin、Saya Hideyuki、Namwat Nisana
  • Journal Title: Frontiers in Pharmacology Volume: 13 Pages: 897368-897368
  • DOI: 10.3389/fphar.2022.897368
  • Peer Reviewed
• [Journal Article] Regulatory roles of fibronectin and integrin α5 in reorganization of the actin cytoskeleton and completion of adipogenesis (2022)
  • Author(s): Uetaki Megumi、Onishi Nobuyuki、Oki Yoshinao、Shimizu Takatsune、Sugihara Eiji、Sampetrean Oltea、Watanabe Takashi、Yanagi Hisano、Suda Kiyoshi、Fujii Hiroya、Kano Koichiro、Saya Hideyuki、Nobusue Hiroyuki
  • Journal Title: Molecular Biology of the Cell Volume: 33 Issue: 9
  • DOI: 10.1091/mbc.e21-12-0609
  • Peer Reviewed / Open Access
• [Journal Article] Tumor-specific inter-endothelial adhesion mediated by FLRT2 facilitates cancer aggressiveness (2022)
  • Author(s): Ando T, Tai-Nagara I, Sugiura Y, Kusumoto D, Okabayashi K, Kido Y, Sato Kohji, Saya H, Navankasattusas S, Li DY, Suematsu M, Kitagawa Y, Seiradake E, Yamagishi S, *Kubota Y.
  • Journal Title: J Clin Invest Volume: 132 Issue: 6 Pages: 153626-153626
  • DOI: 10.1172/jci153626
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Presence of spontaneous epithelial-mesenchymal plasticity in esophageal cancer (2022)
  • Author(s): Tsuchihashi Kenji、Hirata Yuki、Yamasaki Juntaro、Suina Kentaro、Tanoue Kenro、Yae Toshifumi、Masuda Kenta、Baba Eishi、Akashi Koichi、Kitagawa Yuko、Saya Hideyuki、Nagano Osamu
  • Journal Title: Biochemistry and Biophysics Reports Volume: 30 Pages: 101246-101246
  • DOI: 10.1016/j.bbrep.2022.101246
  • Peer Reviewed / Open Access
• [Journal Article] N-cadherin upregulation mediates adaptive radioresistance in glioblastoma (2021)
  • Author(s): Osuka Satoru、Zhu Dan、Zhang Zhaobin、Li Chaoxi、Stackhouse Christian T.、Sampetrean Oltea、Olson Jeffrey J.、Gillespie G. Yancey、Saya Hideyuki、Willey Christopher D.、Van Meir Erwin G.
  • Journal Title: Journal of Clinical Investigation Volume: 131 Issue: 6
  • DOI: 10.1172/jci136098
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lactate Reprograms Energy and Lipid Metabolism in Glucose-Deprived Oxidative Glioma Stem Cells (2021)
  • Author(s): Minami Noriaki、Tanaka Kazuhiro、Sasayama Takashi、Kohmura Eiji、Saya Hideyuki、Sampetrean Oltea
  • Journal Title: Metabolites Volume: 11 Issue: 5 Pages: 325-325
  • DOI: 10.3390/metabo11050325
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MEK inhibition preferentially suppresses anchorage‐independent growth in osteosarcoma cells and decreases tumors in vivo (2021)
  • Author(s): Shimizu Takatsune、Kimura Kiyomi、Sugihara Eiji、Yamaguchi‐Iwai Sayaka、Nobusue Hiroyuki、Sampetrean Oltea、Otsuki Yuji、Fukuchi Yumi、Saitoh Kaori、Kato Keiko、Soga Tomoyoshi、Muto Akihiro、Saya Hideyuki
  • Journal Title: Journal of Orthopaedic Research Volume: - Issue: 12 Pages: 2732-2743
  • DOI: 10.1002/jor.25023
  • Peer Reviewed / Open Access
• [Journal Article] TGFβ Signaling Activated by Cancer-Associated Fibroblasts Determines the Histological Signature of Lung Adenocarcinoma (2021)
  • Author(s): Sato Ryo、Imamura Kosuke、Semba Takashi、Tomita Yusuke、Saeki Sho、Ikeda Koei、Komohara Yoshihiro、Suzuki Makoto、Sakagami Takuro、Saya Hideyuki、Arima Yoshimi
  • Journal Title: Cancer Research Volume: 81 Issue: 18 Pages: 4751-4765
  • DOI: 10.1158/0008-5472.can-20-3941
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The membrane-linked adaptor FRS2β fashions a cytokine-rich inflammatory microenvironment that promotes breast cancer carcinogenesis (2021)
  • Author(s): Takeuchi Yasuto、Kimura N、Murayama T、Machida Y、Iejima D、Nishimura T、Terashima M、Wang Y、Li M、Sakamoto R、Yamamoto M、Itano N、Inoue Y、Ito M、Yoshida N、Inoue J、Akashi K、Saya H、Fujita K、Kuroda M、Kitabayashi I、Voon D、Suzuki Takeshi、Tojo A、Gotoh Noriko
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 118 Issue: 43 Pages: 1-12
  • DOI: 10.1073/pnas.2103658118
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Oncogenic KRAS?expressing organoids with biliary epithelial stem cell properties give rise to biliary tract cancer in mice (2021)
  • Author(s): Kasuga Akiyoshi、Semba Takashi、Sato Ryo、Nobusue Hiroyuki、Sugihara Eiji、Takaishi Hiromasa、Kanai Takanori、Saya Hideyuki、Arima Yoshimi
  • Journal Title: Cancer Science Volume: 印刷中 Issue: 5 Pages: 1822-1838
  • DOI: 10.1111/cas.14703
  • Peer Reviewed / Open Access
• [Journal Article] Molecular and cellular mechanisms underlying brain metastasis of breast cancer (2020)
  • Author(s): Hosonaga Mari、Saya Hideyuki、Arima Yoshimi
  • Journal Title: Cancer and Metastasis Reviews Volume: 39 Issue: 3 Pages: 711-720
  • DOI: 10.1007/s10555-020-09881-y
  • Peer Reviewed / Open Access
• [Journal Article] Targeting of cancer stem cells by differentiation therapy (2020)
  • Author(s): Arima Yoshimi、Nobusue Hiroyuki、Saya Hideyuki
  • Journal Title: Cancer Science Volume: 111 Issue: 8 Pages: 2689-2695
  • DOI: 10.1111/cas.14504
  • Peer Reviewed / Open Access
• [Journal Article] 2-Nitroimidazoles induce mitochondrial stress and ferroptosis in glioma stem cells residing in a hypoxic niche (2020)
  • Author(s): Koike Naoyoshi、Kota Ryuichi、Naito Yoshiko、Hayakawa Noriyo、Matsuura Tomomi、Hishiki Takako、Onishi Nobuyuki、Fukada Junichi、Suematsu Makoto、Shigematsu Naoyuki、Saya Hideyuki、Sampetrean Oltea
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 450-462
  • DOI: 10.1038/s42003-020-01165-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Inhibitor of Apoptosis Protein Livin Confers Resistance to Fas-Mediated Immune Cytotoxicity in Refractory Lymphoma (2020)
  • Author(s): Sugihara Eiji、Hashimoto Norisato、Osuka Satoru、Shimizu Takatsune、Ueno Sayaka、Okazaki Shogo、Yaguchi Tomonori、Kawakami Yutaka、Kosaki Kenjiro、Sato Taka-Aki、Okamoto Shinichiro、Saya Hideyuki
  • Journal Title: Cancer Research Volume: 80 Issue: 20 Pages: 4439-4450
  • DOI: 10.1158/0008-5472.can-19-3993
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Blood and lymphatic systems are segregated by the FLCN tumor suppressor (2020)
  • Author(s): Tai-Nagara I, Hasumi Y, Kusumoto D, Hasumi H, Okabe K, Ando T, Matsuzaki F, Itoh F, Saya H, Liu C, Li W, Mukouyama Y, Linehan WM, Liu X, Hirashima M, Suzuki Y, Funasaki S, Satou Y, Furuya M, Baba M, Kubota Y.
  • Journal Title: Nat. Commun. Volume: 11 Issue: 1 Pages: 6314-6314
  • DOI: 10.1038/s41467-020-20156-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lung Adenocarcinoma Mouse Models Based on Orthotopic Transplantation of Syngeneic Tumor-Initiating Cells Expressing EpCAM, SCA-1, and Ly6d (2020)
  • Author(s): Semba Takashi、Sato Ryo、Kasuga Akiyoshi、Suina Kentaro、Shibata Tatsuhiro、Kohno Takashi、Suzuki Makoto、Saya Hideyuki、Arima Yoshimi
  • Journal Title: Cancers Volume: 12 Issue: 12 Pages: 3805-3805
  • DOI: 10.3390/cancers12123805
  • Peer Reviewed / Open Access
• [Presentation] Therapeutic strategies based on actin cytoskeleton dynamics for targeting chemoresistant osteosarcoma stem cells (2022)
  • Author(s): 信末博行, 清水孝恒, 高橋信博, 山口さやか, 杉原英志, 大西伸幸, 佐谷秀行
  • Organizer: 第12回 日米癌合同会議
  • Int'l Joint Research
• [Presentation] Inhibition of MKL1 enhances the effects of anticancer drugs in chemoresistant osteosarcoma cells (2022)
  • Author(s): 信末博行, 清水孝恒, 高橋信博, 山口さやか, 杉原英志, 大西伸幸, 佐谷秀行
  • Organizer: 第81回 日本癌学会学術総会