Abstract 6007: Post-fasting refeeding enhances intestinal stem cell-mediated regeneration and tumorigenesis

Abstract

Abstract Although short-term fasting interventions improve intestinal stem cell (ISC) function, little is known about how much of this benefit comes from fasting versus the post-fasting refeeding response. Given the central role that ISCs play in driving injury-induced repair and in initiating early intestinal tumors, it is possible that fasting by boosting ISC function not only improves regeneration but also unexpectedly elevates intestinal tumorigenesis. To understand how fasting/refeeding interventions influence the role of ISCs in regeneration and early tumor formation, we assessed the function of ISCs to repair the intestinal lining after injury and to contribute to intestinal tumors. Notably, we find that 24 hours post-fasting refeeding boosts intestinal stem and progenitor cells proliferation and increases ISC function in organoid and in fate mapping assays compared to AL and fasted cohorts. Mechanistically, elevated mammalian target of rapamycin (mTOR) activity mediates the effects of refeeding in ISCs as treatment with mTOR inhibitor blocks these effects. Surprisingly, loss of the APC tumor suppressor gene in ISCs increased intestinal tumor numbers in the refed state compared to the AL and fasted states in an mTOR dependent manner. We propose that refeeding through mTOR signaling stimulates ISC function and in a context-dependent manner this can either improve repair after injury or promote intestinal tumorigenesis. Citation Format: Shinya Imada. Post-fasting refeeding enhances intestinal stem cell-mediated regeneration and tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6007.