Molecular mechanism of activation of myofibroblasts and cancer associated fibroblasts in fibrotic liver

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16444
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kyoto University
• Principal Investigator: Nishio Takahiro 京都大学, 医学研究科, 助教 (20899215)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 肝細胞癌 / 癌微小環境 / 癌関連線維芽細胞 / 肝線維化 / 肝硬変

Outline of Final Research Achievements

This study focused on the function of cancer-associated fibroblasts (CAFs) in the tumor microenvironment of hepatocellular carcinoma (HCC) by spatial transcriptome (Visium) analysis using an experimental animal model and human HCC specimens. First, we established an experimental animal model of CAF-induced hepatocarcinogenesis. Visium analysis of mouse liver sections showed that the tumors were composed of heterogeneous cell populations, and that there were characteristic differences in gene expression depending on the different causes of liver injury. We next validated the gene expression profile of CAFs by Visium analysis on tissue sections of human HCC. CAFs co-expressing Col1a1 and Acta2 were clustered by localization and gene expression in tumor tissue. It was suggested that CAFs were potentially originate from the myofibroblasts in the background liver, and were associated with the regulation of not only tumor proliferation, but also immune response and immune evasion.

Free Research Field

肝癌外科治療

Academic Significance and Societal Importance of the Research Achievements

肝癌に対する複合免疫療法の発達に伴い、肝癌微小環境と癌免疫の病態が着目されている。
本研究は肝癌微小環境における癌関連線維芽細胞(CAF)が、腫瘍増殖、癌免疫修飾に対して及ぼす影響について、動物実験モデルとヒト臨床検体を用いて検証を行った。空間トランスクリプトーム解析を行うことで、CAFの組織構築における遺伝子発現によってクラスター化することで、CAFの機能的分類を解明した。CAFは背景肝のmyofibroblastを起源とし腫瘍増殖と癌免疫に影響することが示唆され、将来的なmyofibroblast/CAFを標的とした新たな治療戦略の開発に発展できる可能性がある。