Characterization of a murine pancreatic ductal adenocarcinoma (PDAC) model with tamoxifen inducible pancreas-specific blockade of transforming growth factor-beta (TGF-beta) signaling with KrasG12D expression

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a five-year overall survival of less than 10%. The lack of effective therapeutic strategies for PDAC necessitates the development of models to better understand the disease. Transforming growth factor-β (TGFβ)-SMAD4 signaling plays a critical role in PDAC development with more than half of all patients either have mutated SMAD4 (loss of function) or altered type II TGF TGFβ -receptor (Tgfbr2) gene. Here we present a murine model of PDAC with Tamoxifen induced conditional deletion of the TGFβ-receptor 2 (Tgfbr2) gene and expression of an activating KrasG12D mutation in pancreatic acinar cells. LSL-KrasG12D/+; Tgfbriifl/fl; Ptf1a-CreER mice were generated by crossing Ptf1aCre-ERTM mice with LSL-KrasG12D mice in which expression of KrasG12D is restrained by a lox-stop-lox cassette until Cre activation by tamoxifen injection. These mice were then bred with Tgfbr2fl/fl mice with loxP sites flanking exon 4 of the Tgfbr2 allele to block TGFβ-SMAD4 signaling. 18Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography was performed to detect tumors and measure their metabolic volumes and standard uptake values over time. This model showed a latency of approximately 16-20 weeks following 5 i.p. injections of tamoxifen (~75 mg/kg in corn oil). Follow-up on the survival of the mice post tamoxifen injections showed the median survival of 252 days in male and 234 days in female mice. Histological evaluation showed multifocal nodules of neoplasia composed of tubules and acini with cuboidal to polygonal cells. Carcinoma cells were positive for cytokeratin 19 and for mucins identified by Alcian blue staining, both confirming the ductal phenotype of these tumors. Picrosirius red staining demonstrated dense stromal desmoplasia which recapitulates human disease. Flow cytometric evolution of the immune microenvironment was also done to evaluate the infiltration of immune cells. Additional characterization of our novel mouse model of pancreatic cancer is underway to understand PDAC progression and develop effective therapeutic approaches. Citation Format: Sanjay Pandey, Brett Bell, Claudia G. Chavez, Wade Koba, Talicia Savage, Patrik Asp, Indranil Basu, Chandan Guha. Characterization of a murine pancreatic ductal adenocarcinoma (PDAC) model with tamoxifen inducible pancreas-specific blockade of transforming growth factor-β (TGF-β) signaling with KrasG12D expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 938.