KRASG12D and TP53R167H cooperate to induce pancreatic carcinoma in conditional transgenic Sus scrofa

D. Principe, N. Overgaard, A. Diaz, C. Torres, R. McKinney, D. Dawson, L. Rund, R. Schwind, P.J. Grippo, L. Schook.
American Association for Cancer Research Annual Meeting, April 1-5 2017, Washington D.C.

Although survival has improved in recent years, pancreatic ductal adenocarcinoma (PDAC) remains remarkably virulent with a median survival time of only four months. As there is no effective strategy for the management of PDAC, there is a need for the development of new preclinical strategies. The majority of this work is being done in genetically modifıed mice, which faithfully recapitulate a variety of pancreatic cancer histotypes. While mice have allowed for unprecedented insight into pancreatic cancer etiology, due to fundamental differences in anatomy and physiology, mouse models of PDAC often fail to accurately predict responsiveness to therapy. As the pig pancreas has more similar anatomical orientation and localization to humans than that of rodents, pigs may serve as a more relevant model for PDAC and other malignancies of the pancreas. As KRAS and TP53 mutations are observed in approximately 95% and 70% of PDAC patients, respectively, we generated Cre/lox transgenic Sus scrofta expressing a LSL-KRASG12D-TP53R167H cassette and administered an AdenoCre particle to the pancreas gland parenchyma. This resulted in a mixed histoype of metastatic leiomysarcoma and neoplastic disease of the pancreas. To produce a similar pancreas histoype while avoiding the leiomyosarcoma, we next restricted the Adeno-Cre administration to the main pancreatic duct, which resulted in both PDAC and neuroendocrine carcinoma with no abnormality of the smooth muscle. This serves as the fırst large animal model of pancreatic carcinogenesis, and given the anatomical/physiological similarity of pigs and humans, may allow for insight into new avenues of research not before possible in rodents.