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.

The intestinal epithelium is a very dynamic tissue under a high regenerative pressure, which makes it susceptible to malignant transformation. Proper integration of various cell signaling pathways and a balanced cross talk between different cell types composing the organ are required to maintain intestinal homeostasis. Dysregulation of this balance can lead to colorectal cancer (CRC). Here, we review important insights into molecular and cellular mechanisms of CRC. We discuss how perturbation in complex regulatory networks, including the Wnt, Notch, BMP, and Hedgehog pathways; and how variations in inflammatory signaling, nutrients, and microbiota can affect intestinal homeostasis contributing to the malignant transformation of intestinal cells. INTESTINE STRUCTURE AND FUNCTION The intestine is the last part of the gastrointestinal tract, and is divided into two anatomically and functionally different sections: the small intestine and the large intestine, whose main functions are food digestion, stool compaction, and absorption of water, nutrients, and salts. Both the small and large intestines present an outer layer of smooth muscle with enteric nervous system; a middle layer composed of connective tissue, nerves, and lymphatic vessels; and an inner epithelial layer called the mucosa. The small intestine presents epithelial folds resembling finger-like protrusions called villi, which face the lumen and aim to maximize the available absorptive area. Villi are surrounded by epithelial invaginations that form the crypts of Lieberkü hn (Figure 1). In contrast, the colonic epithelium lacks villi and consists of a plane surface with multiple epithelial invaginations forming the crypts (

Summary Chromosomal instability (CIN), a type of genomic instability, favors changes in chromosome number and structure and it is associated with the progression and initiation of multiple diseases, including cancer. Therefore, CIN identification and analysis represents a useful tool for cancer diagnosis and treatment. Here, we report an optimized molecular cytogenetic protocol to detect CIN in formalin-fixed, paraffin-embedded mouse and human tissues, using fluorescent in situ hybridization to visualize and quantify chromosomal alterations such as amplifications, deletions, and translocations. For complete information on the generation and use of this protocol, please refer to Brandt et al. (2018) .

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