Abstract A006: Generation of a flexible pancreatic cancer mouse model via somatic tissue engineering

Abstract Pancreatic cancer, recognized as one of the most lethal cancer types, exhibits a dismal five-year survival rate below 12%. The genetic and epigenetic heterogeneity in human cancer poses a tremendous challenge in understanding disease mechanisms and developing targeted therapeutics. Current mouse models in the field can recapitulate some features of human pathophysiology but have limitations. While tumor formation in patients is focal, most genetically engineered mouse models (GEMMs) express oncogenes throughout the pancreas. GEMMs also have limited flexibility to manipulate gene expression and model the heterogeneity of human cancer. Additionally, GEMMs require significant time for crossing and tumor formation. Tumor transplantation models offer greater flexibility, however, they often require immunodeficient mice, which limits their applications in modeling the tumor microenvironment. To overcome the limits of current mouse models, we combined the piggyBac transposon system, CRISPR/Cas9, and in vivo electroporation to engineer somatic pancreatic tissue to induce focal tumor formation in immune-competent mice. With this approach, we engineered wildtype pancreata to express oncogenic KrasG12D while knocking out multiple tumor suppressors. We optimized this protocol by generating multiplexed gRNA constructs and cell type-specific promoters to improve reproducibility. Low-grade tumors formed within 10 days after electroporation, progressed to higher grade within a month, and metastasized to peritoneal organs during disease progression. Mouse tumors also recapitulated histopathological features in human patients. Lastly, we used our novel mouse model to study how mutant Kras disrupts post-transcriptional regulation by microRNA to drive pancreatic tumorigenesis. This model offers a powerful platform for manipulating gene expression and functionality to model cancer heterogeneity, ultimately advancing precision oncology's prospects for treating human patients. Citation Format: Ziyue (Zoey) Yang, Mara Cardenas, Akihiko Miyauchi, Caroline Snider, Ronald Parchem. Generation of a flexible pancreatic cancer mouse model via somatic tissue engineering [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A006.