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

2019 Fiscal Year Final Research Report

• 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
• Keywords: がん関連線維芽細胞 / アクチン細胞骨格 / MKL1

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.

Free Research Field

腫瘍生物学

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。