Elucidation of the mechanism of CAFs-specific cell death induction by FOXO1 inhibition

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K20849
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0901:Oncology and related fields
• Research Institution: Tokyo Dental College
• Principal Investigator: KOYAMA TAKUMI 東京歯科大学, 歯学部, 非常勤歯科医師 (50906386)
• Project Period (FY): 2021-08-30 – 2024-03-31
• Keywords: FOXO1 / CAFs

Outline of Final Research Achievements

We were able to show in vitro that inhibition of FOXO1 in CAFs by AS1842856 suppresses the secretion of cytokines such as TGF-β and SDF-1, which signal the tumor-promoting ability of CAFs. Furthermore, ATAC-seq and metabolome analysis enabled us to narrow down candidates for transcription factors and signals involved in FOXO1 suppression. However, in in vivo co-transplantation experiments of cancer cells and CAFs, it was difficult to suppress only FOXO1 within the tumor, and no results were found suggesting that FOXO1 suppresses the tumor-promoting ability.

Free Research Field

細胞分子生物学

Academic Significance and Societal Importance of the Research Achievements

今回の研究ではFOXO1の機能が抑制されたCAFsにおいて、がん促進性サイトカインなどの産生能が低下することが示され、CAFsのがん促進能も失われていることがin vitroでは示されたが、in vivoにおけるがん細胞との共移植では腫瘍増殖を制御する結果とはならず、今後さらなる動物実験モデルの開発や他因子との関連、シグナルについての探索が急務である。FOXO１抑制に焦点を絞りCAFsに細胞死を誘導する新規CAF標的治療法を動物モデルで開発する点で、国内外の従来の研究と比較し新規性および独創性が高く、より効果的な治療薬の開発が期待される。