Abstract B056: Selective epithelial activation of KRAS G12D mutation drives ductal pancreatic neoplasia in pigs

Abstract

Abstract An innovative approach in pancreatic cancer (PC) research is to utilize large animal models which (i) would be useful for development of technologies that require a human-sized platform and (ii) would produce data that could have greater clinical relevance and accuracy compared to data produced by murine models. To this end, our group has been developing porcine PC models and has reliably induced PC in the KRAS G12D/p53 R167H Oncopig model. The objective of the present study was to generate a slower-growing, early-stage PC model with intraductal injection of adenoviral vector with a Keratin 8 promoter driving the expression of the Cre-Recombinase protein (Ad5mK8-nlsCre) in oncopigs which, we hypothesized, would produce pancreatic neoplasia restricted to the epithelium. Results We first confirmed with scRNA-seq and immunohistochemistry that Keratin-8 expression in the porcine pancreas was restricted to ductal and acinar cells. Using an ex vivo infection assay with the Ad5mK8-nlsCre vector in wild-type porcine pancreas, we then demonstrated that expression of Cre-recombinase was confined to epithelial cells. We then performed a dose-response study of ductal injection (laparotomy) of Ad5mK8-nlsCre (10(7)-10(10) pfu) in Oncopigs. At the planned 2-month endpoint, all Ad5mK8-nlsCre concentrations produced microscopic evidence of ductal hyperplasia, metaplasia, and nuclear atypia, with KRAS-G12D expression by immunohistochemistry. At the higher Ad5mK8-nlsCre concentration, there was increased ductal mucin production. Using an epithelial-specific AdCre vector, we produced microscopic epithelial neoplasia within the pancreas of the Oncopig. Conclusion While further follow-up and characterization is needed, this induction technique may yield a porcine model of early-stage PC, which could be useful to (i) study early tumor biology and progression and (ii) develop diagnostic and interventional technologies for early tumor management. Citation Format: Carlos P. Jara, Al-Murtadha Al-Gahmi, Binh Le, Mark A. Carlson. Selective epithelial activation of KRAS G12D mutation drives ductal pancreatic neoplasia in pigs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B056.