Autophagy provides a quiescent state in colon cancer stem cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K09023
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Teikyo University (2022); National Cancer Center Japan (2020-2021)
• Principal Investigator: Ohata Hirokazu 帝京大学, 先端総合研究機構, 講師 (40570057)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: がん幹細胞

Outline of Final Research Achievements

Cancer tissue represent the intratumoral heterogeneity, and the resistance to anti-cancer therapy is often attributed to slow-cycling persister populations with cancer stem cell (CSC)-like features. We previously identified the heterogeneity in colon CSCs from patient-derived organoids and xenografted tumors and demonstrated that while the NOX1-mTORC1 pathway is responsible for proliferation of a fast-cycling population of cancer cells, PROX1 expression is required for a persister-like slow-cycling population of CSCs. Here we demonstrated that enhanced autophagic activity mediated by mTORC1 inhibition induced PROX1 expression. Induction of PROX1 in turn inhibited NOX1-mediated mTORC1 activation, thus providing the quiescent state via a feedback regulation. Inhibition of autophagy synergized with mTORC1 inhibition to block cancer proliferation.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

大腸がんの根治を目指すためには、治療抵抗性を担う大腸がん細胞を特定し、その細胞を標的とした新しい治療法の開発が強く望まれている。本研究により、静止期にあるがん幹細胞がオートファジー活性が高く、抗がん剤に強い抵抗性を示すことが明らかとなった。また、大腸がんに対する既存の抗がん剤とオートファジー阻害剤の併用により、相乗的に大腸がん細胞の増殖を抑制することがわかった。以上の研究成果は、大腸がんの治療抵抗性の克服、ひいては大腸がんの根治への道標となると考えられる。