Abstract 822: Genetically engineered mouse models of catastrophic pancreatic ductal adenocarcinoma

Abstract

Abstract Carcinogenesis of pancreatic ductal adenocarcinoma (PDAC) has been well studied using genetically engineered mouse (GEM) models with abnormalities in activation of both RAS and E2 factor (E2F)-which is associated with the Rb-E2F pathway, and dysfunction of p53-which is associated with the transformed 3T3 cell double minute 2 (MDM2)-p53 pathway. Catastrophic progression of the malignancy is one of unique manifestation, which has not been recapitulated in the GEMs to study underlined mechanisms, while we have recently reported a new GEM developing PDAC to die in 3 weeks after birth due to the catastrophic progression [Yamaguchi T. et al, J Pathol. 2014; 234(2):228-138]. The GEM had the specific expression of SV40 tsA58 large T antigen (tsTAg) to inhibit p53 and Rb family molecules (Rb1, Rbl1 and Rbl2) on pancreas with the expression of oncogenic Kras (KrasG12D) by Pdx1 promoter-mediated Cre-loxP recombination. In this study, we sought to determine if the induced tsTAg on pancreatic epithelial cells with constitutive KrasG12D expression are enough to develop PDAC and catastrophic manifestation, by the generation of a new GEM based on Cre-loxP recombination and Tet-On system. In the GEM, KrasG12D constitutively expresses on pancreatic epithelial cells after the Cre-loxP recombination under the control Pdx1 promoter, while tsTAg expression can be regulated by Tet-On system after the recombination by Pdx1 promoter. Any of the mice did not developed PDAC within 6 month, but all of the mice developed PDAC by Dox administration in within 1 week and died by the progression of PDAC within 3 weeks after the start.The rapid progression and development of PDAC appeared to be associated with the stronger tsTAg expression depending on reverse tetracycline trans-activator. These results demonstrated that KrasG12D driven PDAC carcinogenesis was promoted by the presence of tsTAg expression, resulting in production of PDAC cells with aggressive growth. In conclusion, our established new mouse model can contribute to increase knowledge about catastrophic PDAC. Citation Format: Takashi Yamaguchi, Sanae K. Ikehara, Hayao Nakanishi, Yuzuru Ikehara. Genetically engineered mouse models of catastrophic pancreatic ductal adenocarcinoma. [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 822. doi:10.1158/1538-7445.AM2015-822