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

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

doi:10.1038/s41598-018-30916-6

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.

Highlights

Modified mouse models have revolutionized cancer research, allowing for faithful and reproducible histotypes closely representing those observed in human patients
The most widely used mouse model of pancreatic cancer consists of concurrent KRASG12D and TP53172H mutations targeted to the exocrine pancreas under the Pdx-1 promoter[10]
To assess the viability of loxp-STOP-loxp (LSL)-KRASG12D-TP53R167H pigs as a potential model of pancreatic ductal adenocarcinoma (PDAC), we first compared the microscopic anatomy of the human, murine, and porcine pancreas

Summary

Introduction

Modified mouse models have revolutionized cancer research, allowing for faithful and reproducible histotypes closely representing those observed in human patients This is true in recent years, largely attributed to the availability of mix-and-match systems such as Cre/lox and tTA/TRE1. Pig pancreata generally exhibit three distinct lobes, with the duodenal lobe corresponding to the head of the human pancreas, the connecting lobe being analogous to the uncinate process, and the splenic lobe corresponding to the tail/body of the pancreas[9] In light of these many similarities, modeling pancreatic cancer in pigs would provide the opportunity to conduct surgical and radiologic studies never before possible, and may offer additional insight into disease pathogenesis due to the size and composition of the gland. Following refinement of the delivery system, these mutations successfully induced pancreatic neoplasms and cancer in the pig, providing the first documented large animal model of pancreatic carcinoma

Methods

Results

Conclusion