Elucidation of underlyingmechanism of MKL1-mediated induction of cancer associated fibroblasts and its clinical applications

• Project/Area Number: 17H01401
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Keio University
• Principal Investigator: Saya Hideyuki 慶應義塾大学, 医学部(信濃町), 教授 (80264282)
• Co-Investigator(Kenkyū-buntansha): 信末 博行 慶應義塾大学, 医学部(信濃町), 特任助教 (90525685)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥42,640,000 (Direct Cost: ¥32,800,000、Indirect Cost: ¥9,840,000); Fiscal Year 2019: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000); Fiscal Year 2018: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000); Fiscal Year 2017: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
• Keywords: がん関連線維芽細胞 / アクチン細胞骨格 / MKL1 / 癌関連線維芽細胞 / 骨肉腫 / MKL / アクチン / がん微小環境 / 腫瘍関連線維芽細胞 / 微小環境 / 分化 / 腫瘍微小環境 / Rhoキナーゼ阻害剤

Outline of Final Research Achievements

In various stromal cells (fibroblasts, mesenchymal progenitor cells, and adipocytes), conditioned medium obtained from cultured osteosarcoma cells enhanced the activation of megakaryoblastic leukemia 1 (MKL1) which is a transcriptional regulator as well as induced the transition of these cells to cancer-associated fibroblasts (CAFs). We induced expression of MKL1 in various stromal cells and found that they increased expression of CAF-related genes and acquired CAF phenotypes. We also found that the interaction with serum response factor (SRF) is required for MKL1-induced CAF differentiation. In addition, we found that Rho-kinase inhibitor fasudil prevented nuclear translocation of MKL1 via actin dynamics and suppressed CAF differentiation as well as tumor formation in mouse osteosarcoma model. These findings suggest that MKL1 is a master regulator of the transition of stromal cells to CAFs and blocking CAF differentiation may provide a novel therapeutic approach for cancers.

Academic Significance and Societal Importance of the Research Achievements

転写因子あるいは転写制御シグナルを標的とした薬剤が見出されていない現状において、本研究成果は、アクチン細胞骨格の動態を低分子化合物によって変化させることでMKL1および転写因子を調節し、それによって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

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  • Author(s): Kunitomi H, Oki Y, Onishi N, Kano K, Banno K, Aoki D, Saya H, Nobusue H
  • Journal Title: Genes to Cells Volume: 25 Issue: 3 Pages: 165-174
  • DOI: 10.1111/gtc.12747
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rock inhibition suppresses osteosarcoma tumorigenesis by inducing terminal adipocyte differentiation in chemoresistant stemlike cells (2019)
  • Author(s): 1.Takahashi N, Nobusue H, Shimizu T, Sugihara E, Yamaguchi-Iwai S, Onishi N, Kunitomi H, Kuroda T, Saya H
  • Journal Title: Cancer Research Volume: in press Issue: 12 Pages: 3088-3099
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• [Journal Article] Inhibiting xCT Improves 5-Fluorouracil Resistance of Gastric Cancer Induced by CD44 Variant 9 Expression. (2018)
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• [Journal Article] T-type Calcium Channels Determine the Vulnerability of Dopaminergic Neurons to Mitochondrial Stress in Familial Parkinson Disease (2018)
  • Author(s): Tabata Yoshikuni、Imaizumi Yoichi、Sugawara Michiko、Andoh-Noda Tomoko、Banno Satoe、Chai MuhChyi、Sone Takefumi、Yamazaki Kazuto、Ito Masashi、Tsukahara Kappei、Saya Hideyuki、Hattori Nobutaka、Kohyama Jun、Okano Hideyuki
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  • Peer Reviewed / Open Access
• [Journal Article] Synthetic lethality of the ALDH3A1 inhibitor dyclonine and xCT inhibitors in glutathione deficiency-resistant cancer cells (2018)
  • Author(s): Okazaki Shogo、Shintani Subaru、Hirata Yuki、Suina Kentaro、Semba Takashi、Yamasaki Juntaro、Umene Kiyoko、Ishikawa Miyuki、Saya Hideyuki、Nagano Osamu
  • Journal Title: Oncotarget Volume: 9 Issue: 73 Pages: 33832-33843
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  • Peer Reviewed / Open Access
• [Journal Article] EGFR promotes glioma progression by regulating xCT and GluN2B-containing NMDA receptor signaling. (2018)
  • Author(s): Suina K, Tsuchihashi K, Yamasaki J, Kamenori S, Shintani S, Hirata Y, Okazaki S, Sampetrean O, Baba E, Akashi K, Takahashi F, Takahashi K, Saya H, Nagano O.
  • Journal Title: Cancer Science Volume: 109 Issue: 12 Pages: 3874-3882
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  • Peer Reviewed / Open Access
• [Journal Article] Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent. (2018)
  • Author(s): Fujimori K, Ishikawa M, Otomo A, Atsuta N, Nakamura R, Akiyama T, Hadano S, Aoki M, Saya H, Sobue G, Okano H.
  • Journal Title: Nat Med. Volume: 24 Issue: 10 Pages: 1579-1589
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  • Peer Reviewed
• [Journal Article] Metabolic heterogeneity and plasticity of glioma stem cells in a mouse glioblastoma model (2018)
  • Author(s): Shibao S、Minami N、Koike N、Fukui N、Yoshida K、Saya H、Sampetrean O
  • Journal Title: Neuro-Oncology Volume: 20 Issue: 3 Pages: 343-354
  • DOI: 10.1093/neuonc/nox170
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B cell acute leukemia. (2017)
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  • Journal Title: Blood Volume: 129 Issue: 14 Pages: 1958-1968
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  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activation of Transforming Growth Factor Beta 1 Signaling in Gastric Cancer-associated Fibroblasts Increases Their Motility, via Expression of Rhomboid 5 Homolog 2, and Ability to Induce Invasiveness of Gastric Cancer Cells. (2017)
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  • Journal Title: Gastroenterology Volume: in press Issue: 1 Pages: 191-204
  • DOI: 10.1053/j.gastro.2017.03.046
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Phase 1 study of sulfasalazine and cisplatin for patients with CD44v-positive gastric cancer refractory to cisplatin (EPOC1407). (2017)
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  • Journal Title: Gastric Cancer Volume: 20 Issue: 6 Pages: 1004-1009
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  • NAID: 40021377421
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inflammatory mediator ultra-low-molecular-weight hyaluronan triggers necrosis of B-precursor leukemia cells with high surface CD44 expression. (2017)
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  • Journal Title: Cell Death and Disease Volume: 8 Issue: 6 Pages: e2857-e2857
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  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The impact of EpCAM expression on response to chemotherapy and clinical outcomes in patients with epithelial ovarian cancer. (2017)
  • Author(s): Tayama S, Motohara T, Narantuya D, Li C, Fujimoto K, Sakaguchi I, Tashiro H, Saya H, Nagano O, Katabuchi H
  • Journal Title: Oncotarget Volume: 8 Issue: 27 Pages: 44312-44325
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  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ：Calcitriol exerts an anti-tumor effect in osteosarcoma by inducing the endoplasmic reticulum stress response. (2017)
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• [Journal Article] cRGD peptide installation on cisplatin-loaded nanomedicines enhances efficacy against locally advanced head and neck squamous cell carcinoma bearing cancer stem-like cells (2017)
  • Author(s): Miyano Kazuki、Cabral Horacio、Miura Yutaka、Matsumoto Yu、Mochida Yuki、Kinoh Hiroaki、Iwata Caname、Nagano Osamu、Saya Hideyuki、Nishiyama Nobuhiro、Kataoka Kazunori、Yamasoba Tatsuya
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• [Journal Article] Phase I study of salazosulfapyridine in combination with cisplatin and pemetrexed for advanced non-small-cell lung cancer. (2017)
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  • Journal Title: Cancer Science Volume: 108 Issue: 9 Pages: 1843-1849
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  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reducing Inflammatory Cytokine Production from Renal Collecting Duct Cells by Inhibiting GATA2 Ameliorates Acute Kidney Injury. (2017)
  • Author(s): Yu L, Moriguchi T, Kaneko H, Hayashi M, Hasegawa A, Nezu M, Saya H, Yamamoto M, Shimizu R.
  • Journal Title: Molecular and Cellular Biology Volume: 37 Issue: 22 Pages: 211-217
  • DOI: 10.1128/mcb.00211-17
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stat3 as a potential therapeutic target for rheumatoid arthritis. (2017)
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  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 10965-10965
  • DOI: 10.1038/s41598-017-11233-w
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• [Journal Article] Organotypic brain explant culture as a drug evaluation system for malignant brain tumors (2017)
  • Author(s): Minami N、Maeda Y、Shibao S、Arima Y、Ohka F、Kondo Y、Maruyama K、Kusuhara M、Sasayama T、Kohmura E、Saya H、Sampetrean O
  • Journal Title: Cancer Medicine Volume: 6 Issue: 11 Pages: 2635-2645
  • DOI: 10.1002/cam4.1174
  • NAID: 120006373813
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Role of actin dynamics in cell fate plasticity of microenvironmental cells (2019)
  • Author(s): Hideyuki Saya
  • Organizer: 11th AACR-JCA Joint Conference on Breakthroughs in Cancer Research: Biology to Precision Medicine
  • Int'l Joint Research / Invited
• [Remarks] 慶應義塾大学医学部 先端医科学研究所 遺伝子制御研究部門ホームページ
  • URL: http://www.genereg.jp