Pancreatic cancer is among the deadliest human malignancies ranking 4th in the United States for cancer-related deaths among both men and women. Due to the invasive nature of pancreatic cancer, metastasis to the lymphatic system and distant organs is a major contributor to pancreatic cancer-related death. Genetic alterations in cell adhesion molecules contribute to human disease including developmentally related syndromes and cancer. In a sequencing study of 24 primary pancreatic tumor exomes published by the Hopkins pancreatic cancer team in 2008, 79% of tumors had at least one mutation in a homophilic cell adhesion molecule, and this class of molecules was named as one of the twelve core signaling pathways in pancreatic cancer. Among this class of cell adhesion molecules are adherens junctions. Mislocalization of the adherens protein p120 catenin has been identified in almost all of the major types of human carcinomas including pancreatic cancer. An accumulating body of evidence has identified p120 catenin as a prognostic marker in pancreatic cancer. Based on relevant literature, we hypothesize that misexpression and mislocalization of p120 catenin in pancreatic cancer is pathologic in the progression of this deadly disease. To test this hypothesis, we have ablated p120 catenin in the KCiMist1 mouse model of pancreatic cancer. The KCiMist1 mouse model activates oncogenic Kras in adult pancreatic acinar cells and displays the preinvasive PanIN 1 - PanIN 3 lesions in a manner that faithfully recapitulates the human disease. Homozygous deletion of p120 catenin in this model resulted in an almost complete replacement of acinar cells by acinar to ductal metaplastic lesions, accelerated PanIN formation, and stromal infiltration at 1 month. At 2 months, the stromal infiltrate persists, and we see considerable evidence of fibrosis and fatty deposition in the pancreas, which are pathologic features of pancreatitis. We used the KCiMist1Gp120f/f model to trace the lineage of acinar cells undergoing Kras activation and p120 catenin excision, and observed a marked increase in isolated GFP+ Ecadherin+ cells located in the extensive stroma at 1 and 2 months suggesting that p120 catenin normally restrains PanIN epithelial cell delamination. We have begun to study potential mechanisms for this delamination phenotype including epithelial-mesenchymal transition (EMT) and non-EMT based mechanisms. Research suggests that EMT is a contributing factor to the development of drug resistance, which makes EMT a promising target for the development of future therapies that reduce invasion and drug resistance leading to better prognosis for patients with pancreatic cancer. Our preliminary findings suggest that the KCiMist1Gp120f/f mouse model represents a valuable tool to study both EMT and non-EMT based mechanisms for PanIN epithelial cell delamination.

Citation Format: Audrey M. Hendley, Jennifer M. Bailey, Janivette Alsina, Christine Iacobuzio-Donahue, Anirban Maitra, Albert Reynolds, Steven D. Leach. p120 catenin: A novel regulator of PanIN epithelial cell delamination in preinvasive pancreatic cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 66. doi:10.1158/1538-7445.AM2014-66