mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis

Dietary habits that can induce inflammatory bowel disease (IBD) are major colorectal cancer (CRC) risk factors, but mechanisms linking nutrients, IBD, and CRC are unknown. Using human data and mouse models, we show that mTORC1 inactivation-induced chromosomal instability impairs intestinal crypt proliferation and regeneration, CDK4/6 dependently. This triggers interleukin (IL)-6-associated reparative inflammation, inducing crypt hyper-proliferation, wound healing, and CRC. Blocking IL-6 signaling or reactivating mTORC1 reduces inflammation-induced CRC, so mTORC1 activation suppresses tumorigenesis in IBD. Conversely, mTORC1 inactivation is beneficial in APC loss-dependent CRC. Thus, IL-6 blockers or protein-rich-diet-linked mTORC1 activation may prevent IBD-associated CRC. However, abolishing mTORC1 can mitigate CRC in predisposed patients with APC mutations. Our work reveals mTORC1 oncogenic and tumor-suppressive roles in intestinal epithelium and avenues to optimized and personalized therapeutic regimens for CRC. [Display omitted] •mTORC1 activity is important for intestinal tissue homeostasis and regeneration•mTORC1 inactivation-induced DNA damage and CIN trigger IL-6 -dependent CRC•mTORC1 inactivation reduces tumor incidence in mouse models with APC inactivation•mTORC1 inactivation correlates with inflammation in colitis-induced CRC patients Brandt et al. shed light on the mechanisms linking nutrients, inflammation, and colorectal cancer (CRC) and show that mTORC1 inactivation promotes CRC in a colitis mouse model, but reduces tumorigenesis in mice with APC inactivation, demonstrating mTORC1’s oncogenic and tumor-suppressive roles in the intestinal epithelium.