Diminished noncanonical NF-kappa B signaling induces colitis-associated colorectal cancer susceptibility upon de-differentiation of epithelial cells

Abstract Patients with a medical history of Inflammatory Bowel Disease are predisposed to developing colitis-associated colorectal cancer (CAC), with greater than 20% developing CAC within 30 years of disease onset. CAC is a form of inflammation-induced tumorigenesis, where unregulated inflammation causes cells in the colon to accumulate mutations poising them for neoplasia. We demonstrate that NF-κB inducing kinase (NIK) is a critical regulator of intestinal epithelial cell (IEC) regeneration. We hypothesize that IECs exposed to chronic inflammatory conditions mitigated by dysregulated noncanonical NF-κB signaling are most prone to mutagenesis and cancer-initiating events termed Top-down tumorigenesis. In CAC, NIK depletion results in the accumulation of mature IECs that are increasingly susceptible to mutation and neoplastic transformation. This suggests that terminally differentiated IECs dedifferentiate into a stem-like phenotype. Our work has clinical relevancy, where human CAC biopsy samples have diminished noncanonical NF-κB signaling and NIK (MAP3K14) gene expression. Murine models with NIK deletion in IECs have increased susceptibility to inflammation-induced tumorigenesis following the chemical induction of AOM/DSS to induce colitis. Our mechanistic studies evaluating crypts demonstrate accumulation of mature, non-dividing IECs, which are more susceptible to mutations and malignant transformation. Here, we present a novel role for noncanonical NF-κB signaling in regulating intestinal epithelial cell turnover in protecting against CAC development. Focusing on the key niche signaling interplay following noncanonical NF-κB dysregulation gives greater insight into the CAC tumor microenvironment. Supported by grants from the iTHRIVE Pilot Translational and Clinical Studies Program, VCOM Center for One Health Research, Virginia Tech Carilion Research Acceleration Program, and the Virginia-Maryland College of Veterinary Medicine.