GS26 - Role of Noncanonical NF-kB Signaling in The Development of Intestinal Cell Subpopulations

Introduction/Purpose:
Colorectal cancer (CRC) is a serious, life-threatening sequelae to ulcerative colitis, one form of inflammatory bowel disease. Patients are at an increased risk of developing CRC eight to ten years after their initial UC diagnosis. Colorectal cancer is the fourth most common type of cancer and the second leading cause of cancer-related deaths in the United States. One pathway that is heavily implicated in CRC is NF-kB, a master transcriptional regulator of genes related to proliferation, survival, immunity, and inflammation. Previous studies have demonstrated the anti-inflammatory and anti-neoplastic role of the canonical NF-kB signaling pathway in CRC. NF-kB has been shown to be extensively down regulated in CRC of both mice and humans. However, relatively little is known about the non-canonical NF-kB signaling cascade (activation of Nik).

Methods or Case Description:
To further understand NF-kB/Nik involvement in colon cancer development and progression, we will grow murine intestinal organoids extracted from wild type (Nikloxp) and Nik-/- mice and characterize their growth and development in comparison with WT. Our research hopes to further characterize this aggressive and deadly disease. We hypothesize that loss of non-canonical NFκB signaling attenuates stem cell regeneration of the epithelial cell barrier and/or inhibits cell death in mature epithelial cells in the colon. We further postulate that either of these events are significant contributors to the progression of colorectal cancer and may contribute to tumorigenesis through either a stem cell or enterocyte dependent mechanism. We hope to further identify the cell composition and 3D architecture of these NF-kB low organoids to better understand how NF-kB is implicated in the development of CRC.

Outcomes:
The results of our study suggest that the loss of NIK corresponds with increased inflammation and diminished integrity of the colonic mucosa. The increased expression of Glycoprotein-2 (GP2) along with the decreased expression of Villin, Mucin-2 (MUC2), and Chromogranin A are associated with dysplastic changes underlying the development of colorectal cancer.

Conclusion:
The inflammatory microenvironment induced by dysregulation of the non-canonical pathway requires further attention to illuminate components suitable for inhibition to improve the outcomes for patients with non-canonical induced inflammatory bowel disease and CRC.