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

2022 Fiscal Year Final Research Report

• 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
• Keywords: 腫瘍関連線維芽細胞 / アクチン

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.

Free Research Field

腫瘍生物学

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。