Abstract 5148: NR5A2 is essential for pancreas development and affects pancreas carcinogenesis

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers today. A genome-wide association study (GWAS) has implicated the nuclear receptor NR5A2 in modulating risk for pancreatic cancer. While a role for this gene in pancreatic cancer has not been previously recognized, it plays an important role in stem cell pluripotency and metabolism. Using the zebrafish model, we demonstrate that genetic or pharmacologic inhibition of nr5a2 activity results in absence of exocrine pancreas, while leaving endocrine pancreas unaffected, indicating an essential role in pancreas organ formation. Further, we localize nr5a2 expression to the endodermal bud that gives rise to the exocrine pancreas, consistent with a role for nr5a2 in regulating differentiation of pancreas progenitors. In resected human PDAC specimens and in vitro cell lines, we find that NR5A2 expression is altered compared to normal ductal epithelium. Moreover, shRNA knockdown of NR5A2 dramatically alters proliferation of PDAC cell lines, supporting the hypothesis that NR5A2 is involved in pancreatic carcinogenesis. These data support a model that NR5A2 regulates the proliferation and differentiation of exocrine pancreas progenitor cells during development. We postulate that loss-of-function of NR5A2 results in dysregulation of these processes in the adult pancreas by driving acinar cells to acquire properties of progenitor cells, and therefore is an important step in pancreas oncogenesis. Note: This abstract was not presented at the meeting. Citation Format: Sahar Nissim, Olivia Weeks, John Hedgepeth, Julia Wucherpfennig, Xiao-Xu Wang, Alec Kimmelman, Wolfram Goessling. NR5A2 is essential for pancreas development and affects pancreas carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5148. doi:10.1158/1538-7445.AM2015-5148