KRASG12D and TP53R167H Cooperate to Induce Pancreatic Ductal Adenocarcinoma in Sus scrofa Pigs

Daniel R. Principe, Nana Haahr Overgaard, Alex J. Park, Andrew M. Diaz, Carolina Torres, Ronald McKinney, Matthew J. Dorman, Karla Castellanos, Regina Schwind, David W. Dawson, Ajay Rana, Ajay Maker, Hidayatullah G. Munshi, Lauretta A. Rund, Paul J. Grippo, Lawrence B. Schook*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Although survival has improved in recent years, the prognosis of patients with advanced pancreatic ductal adenocarcinoma (PDAC) remains poor. Despite substantial differences in anatomy, physiology, genetics, and metabolism, the overwhelming majority of preclinical testing relies on transgenic mice. Hence, while mice have allowed for tremendous advances in cancer biology, they have been a poor predictor of drug performance/toxicity in the clinic. Given the greater similarity of sus scrofa pigs to humans, we engineered transgenic sus scrofa expressing a LSL-KRASG12D-TP53R167H cassette. By applying Adeno-Cre to pancreatic duct cells in vitro, cells self-immortalized and established tumors in immunocompromised mice. When Adeno-Cre was administered to the main pancreatic duct in vivo, pigs developed extensive PDAC at the injection site hallmarked by excessive proliferation and desmoplastic stroma. This serves as the first large animal model of pancreatic carcinogenesis, and may allow for insight into new avenues of translational research not before possible in rodents.

Original languageEnglish (US)
Article number12548
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • General

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