VCOM Research Day Program Book 2023

Graduate Student Research Biomedical

11 NF- κ B Inducing Kinase (NIK) Attenuates Top-Down Tumorigenesis During Colorectal Cancer by Regulating Epithelial Cell Proliferation-Differentiation Axis

Holly A. Morrison 1 ; Audrey Rowe 1 ; Kristin Eden 1 ; Daniel E. Rothschild 1 ; Katherine Baumgarner 2 ; Stephan Brown 2 ; Eda Holl 3 ; Irving C. Allen 1 Corresponding author:

1 Virginia-Maryland College of Veterinary Medicine, Blacksburg, 2 Edward Via College of Osteopathic Medicine-Carolinas Campus 3 Duke University, Durham

Patients with a medical history of Inflammatory Bowel Disease are predisposed to colorectal cancer with greater than 20% developing colitis-associated colorectal cancer (CAC) due to inflammation-induced tumorigenesis. Although a hyper-proliferative pool of stem cells in colonic crypts is widely predicted to be the cell-of-origin for CAC, impaired regulation of intestinal epithelial cell (IEC) proliferation is also a critical feature in colorectal cancer development. We hypothesize that proper noncanonical NF-κB signaling requiring stabilization of the NF-κB inducing kinase (NIK) is essential for protection against colorectal cancer and functions through the epithelial cell compartment. Here, we show that NIK attenuates colorectal cancer through the regulation of IEC regeneration and differentiation mediated by noncanonical NF-κB signaling. Murine models with

conditional knockout of NIK in IECs demonstrate increased susceptibility to inflammation-induced tumorigenesis following the chemical induction of AOM/DSS. Mechanistic studies using crypts and organoids further revealed an imbalance of proper apoptosis and proliferation signaling, with colonic crypts having increased accumulation of mature, non-dividing IECs. This suggests a model for Top down tumorigenesis as terminally differentiated IECs lack proper turnover and compensate for decreased regenerative capacity from the stem cell niche by acquiring stem-cell like features. Our work has clinical relevancy as human CAC biopsy samples have diminished noncanonical NF-κB signaling, including significantly decreased gene expression of NIK ( MAP3K14 ) and effector chemokines produced

( CXCL12, CXCL13, CCL19, CCL21 ). Here, we present a novel role for noncanonical NF-κB signaling in regulating IEC regeneration and differentiation in protecting against CAC development and may serve as potential biomarkers for early detection.


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