Abstract 4186: p120 catenin: A novel regulator of epithelial cell delamination in early Kras-driven pancreatic cancer

Abstract

Abstract By 2020, pancreatic cancer is estimated to climb from the 4th to the 2nd most common cause of cancer-related deaths in the United States. This deadly disease has continued to remain largely refractory to chemotherapeutic and treatment regimens, and patients often experience a heavy metastatic burden. A study combining the Sleeping beauty transposon random insertion mutagenesis system with an oncogenic KrasG12D allele in mice as a screen to identify candidate pancreatic cancer genes identified genes enriched in adherens and tight junctions as significantly enriched in Kras-driven neoplasia with Ctnnd1 as a locus commonly mutated in mice developing metastatic progression of pancreatic cancer. Ctnnd1 encodes the adherens junction protein p120 catenin, which is integral in stabilization of cadherin molecules at cell membranes. p120 catenin is misexpressed in an estimated 60% primary pancreatic tumors and low/absent expression levels and predominant cytoplasmic localization of p120 catenin in primary resected pancreatic tumors correlates with worse survival in pancreatic cancer patients. Yet, the mechanisms by which p120 catenin contributes to the pathogenesis of pancreatic cancer are not clear. We have comprehensively examined p120 catenin staining in human Pancreatic Intraepithelial Neoplasia (PanIN) and identified mislocalization of p120 catenin to the cytoplasm as early as PanIN2. 3/5 PanIN3 examined had predominant cytoplasmic staining, which led us to hypothesize that p120 catenin might play a critical role in early pancreatic neoplasia, before the onset of Pancreatic Ductal Adenocarcinoma. To examine the role of p120 catenin during early Kras-driven pancreatic neoplasia, we ablated p120 catenin in a mouse model of preinvasive pancreatic cancer, KCiMist1. KCiMist1p120f/f pancreases display significant acceleration of acinar to ductal metaplasia (ADM) and PanIN formation when compared to KCiMist1p120wt/wt pancreases one month post tamoxifen injection. KCiMist1p120f/f pancreases are significantly larger than KCiMist1p120wt/wt pancreases with 92.89% pancreatic area occupied by Fibrostroma one month post tamoxifen injection. As a result, KCiMist1p120f/f animals have severe exocrine pancreatic insufficiency and die on average 8 weeks earlier than their KCiMist1p120wt/wt controls. Lineage tracing revealed a prominent epithelial cell delamination phenotype in KCiMist1p120f/f pancreases. Quantification of epithelial cells in the extensive stroma revealed a striking 832/7000 CK19+ cells in KCiMist1p120f/f pancreases vs 15/7000 CK19+ cells in KCiMist1p120wt/wt pancreases. Microarray analysis showed >1263 differentially expressed genes! IPA pathway analysis revealed significant gene expression changes in PI3K/AKT and Cdc42 signaling. Taken together, our results suggest a critical role for p120 catenin in regulating epithelial cell delamination in early pancreatic cancer. Citation Format: Audrey M. Hendley, Yue J. Wang, Janivette Alsina, Ishrat Ahmed, Hao Zhang, Samuel Savidge, Hao Ho, Albert Reynolds, Anirban Maitra, Michael Goggins, Christine Iacobuzio-Donahue, Steven D. Leach, Jennifer M. Bailey. p120 catenin: A novel regulator of epithelial cell delamination in early Kras-driven pancreatic cancer. [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 4186. doi:10.1158/1538-7445.AM2015-4186