Abstract 1771: Role of Tsc2-mTORC1 signaling in homeostasis of intestinal epithelium and its relation to inflammation and cancer

Abstract

Abstract Intestinal tumorigenesis driven by mutations in adenomatous polyposis coli gene requires the mammalian target of rapamycin complex 1 (mTORC1) activity, whereas the physiological roles of mTORC1 in the homeostasis of intestinal epithelial cells (IECs) remain virtually unknown. We here generated mice, in which tuberous sclerosis complex 2 (Tsc2), a negative regulator of mTORC1, was specifically ablated in IECs (Tsc2 CKO mice). Tsc2 CKO mice manifested the enhanced proliferative activity of IECs in intestinal crypts as well as the promoted migration of these cells along the crypt-villus axis. In vitro study showed that conditional ablation of Tsc2 in IECs promoted development of intestinal organoids, while mTORC1 inhibitor, rapamycin, diminished this phenotype. Tsc2 CKO mice also manifested the increased apoptotic rate of IECs as well as the increased ectopic Paneth cells, which are one of the major differentiated IECs. In addition, such conditional ablation of Tsc2 resulted in a suppressed expression of Wnt target genes in the colonic epithelium. Finally, we found that Tsc2 CKO mice manifested the increased susceptibility for dextran sulfate sodium (DSS)-induced colitis. Although mTORC1 and Wnt signaling pathways are thought to cooperated to promote oncogenesis in the intestinal epithelium, our results thus suggest that the mTORC1 signaling unexpectedly counter-regulates the Wnt signaling with the maintenance of intestinal homeostasis. Citation Format: Takenori Kotani, Jajar Setiawan, Yoji Murata, Yasuyuki Saito, Takashi Matozaki. Role of Tsc2-mTORC1 signaling in homeostasis of intestinal epithelium and its relation to inflammation and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1771.