Abstract 2729: A genetically engineered mouse model of de novo pancreatic carcinogenesis .

Abstract Multistep models of PDAC development converge on both abnormalities in KRAS and E2F activation, which are part of the Rb/E2F pathway, and dysfunction of p53, which is associated with the MDM2/p53 pathway. Recent progress in the understanding of the protective roles of the Rb/E2F and MDM/p53 pathways against carcinogenesis showed that cross talk and complementary actions of these pathways are present in many types of cancers. In this study, we addressed directly questions regarding the collaborative roles of the Rb/E2F and MDM2/p53 pathways in suppressing the progression of multistep PDAC carcinogenesis by generating TKC (loxP-βgeo-STOP-loxPtemperature-sensitive SV40 T antigen (tsTAg)), loxP-STOP-loxP-KrasG12D, and Pdx1-Cre) mice which exhibit impairment of both pathways and K-rasG12D expression in pancreatic epithelial cells. The PDAC induced in TKC mice exhibited rapid development and absence of inflammation or PanIN formation, which occurred by de novo carcinogenesis. The tumors resembled human PDAC at the histological and molecular level. In in vitro study, we established PDAC cell lines from TKC mice and immortalized pancreatic ductal cell lines from TC mice, Cytokeratin 19 expression with which was applied to select cells as pancreatic ductal cell differentiation. In collagen gel 3D culture, PDAC cells formed atypical gland structures the same as in subcutaneous transplanted tumor in nude mice, while the Cytokeratin 19 positive immortalized ductal cell lines from TC mice formed ductal structures similar to either intralobular or interloblar pancreatic ducts. The results of the analysis of the highlighted molecular mechanisms suggest that the synthetic interaction among mutated Kras, uncontrolled E2f activation, and dysfunction of p53 results in de novo pancreatic carcinogenesis. This model represents an important tool to explore molecular targets for diagnostics and cancer therapy for PDAC via de novo pancreatic carcinogenesis.This work was supported by grants from the Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN) and New Energy and Industrial Technology Development Organization (NEDO) of Japan, and supported in part by Grants-in-Aid for Scientific Research on Priority Area (21590454, 24590498, and 24108006 to Y. I.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Citation Format: Takashi Yamaguchi, Sanae K. Ikehara, Yuzuru Ikehara. A genetically engineered mouse model of de novo pancreatic carcinogenesis . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2729. doi:10.1158/1538-7445.AM2013-2729