Abstract 4151: APC control of retinoic acid suppresses immune cell mediated intestinal proliferative response

Abstract

Abstract Adenomatous polyposis coli (APC) tumor suppressor function is centered on its role in antagonizing Wnt/B-catenin mediated colonic proliferation. Our previous studies, however, established a second role wherein APC's control of retinoic acid (RA) results in intestinal epithelial cell differentiation. Surprisingly, the loss of APC or RA alone in zebrafish embryos was not sufficient to drive nuclear accumulation of B-catenin or intestinal cell proliferation. However, combining APC or RA deficiency with a KRAS mutation was sufficient to induce nuclear localization of B-catenin and the proliferative response. In contrast, the loss of RA alone in adult zebrafish results in both intestinal differentiation defects and proliferation. We were therefore interested in investigating these seemingly contradictory results. Using adult zebrafish, we show for the first time that following loss of retinoic acid adaptive immune cells (but not innate immune cells) are indirectly required to elicit the proliferative response independent of Kras activation. We demonstrate that IL-17 secretion from adaptive immune cells in response to loss of RA predisposes colonic epithelium to inflammation resulting in compromised barrier function, loss of cell polarity, reactivation of a progenitor intestinal program, and proliferation. Importantly, we find in both mouse and human intestinal organoid cultures an evolutionarily shared response with zebrafish of T cell dependent intestinal inflammation and proliferation following loss of RA. Our model demonstrates that loss of RA causes an increase in inflammatory mediators (Cox2 and Prostaglandins) that induces infiltration of IL-17 secreting T cells. In a feed-forward loop, the IL-17 acts on the primed epithelium to up-regulate proliferative signaling mediators (Raf and Rac1). Together, these studies provide an important new perspective on the ordering of molecular events that may underlie colon tumor progression. Citation Format: Amanda K. Templeton, Saher Hammoud, Brad Cairns, David Jones. APC control of retinoic acid suppresses immune cell mediated intestinal proliferative response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4151.