2. Academic Validation
  3. mTORC1 Inactivation Promotes Colitis-Induced Colorectal Cancer but Protects from APC Loss-Dependent Tumorigenesis

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

  • Cell Metab. 2018 Jan 9;27(1):118-135.e8. doi: 10.1016/j.cmet.2017.11.006.
Marta Brandt 1,  Tatiana P Grazioso 1,  Mohamad-Ali Fawal 1,  Krishna S Tummala 1,  Raul Torres-Ruiz 2,  Sandra Rodriguez-Perales 2,  Cristian Perna 3,  Nabil Djouder 4
Affiliations

Affiliations

  • 1 Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
  • 2 Molecular Cytogenetics Unit, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain.
  • 3 Department of Pathology, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid 28034, Spain.
  • 4 Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain. Electronic address: ndjouder@cnio.es.
PMID: 29275959 DOI: 10.1016/j.cmet.2017.11.006
Abstract

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.

Keywords

APC; DNA damage; IL-6; MCRS1; chromosomal instability; colorectal cancer; dNTPs; inflammatory bowel disease; mTORC1; regeneration.

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