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

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.

Porcine Models of Pancreatic Cancer

“…In vivo injection of AdCre directly into the main pancreatic duct of an Oncopig resulted in several nodular tumors after 12 months. Comparison of tumor induced in the OCM pancreas with human PDAC revealed similar morphological features, including a dense desmoplastic stromal reaction that is one key hallmark features of human PDAC ( 75 ). In addition, increased expression of proliferative markers (ERK and PCNA) was present in the OCM pancreatic tumor ( 75 ).…”

“…Primary pancreatic ductal cells were cultured from the OCM and then infected with AdCre; these epithelial cells also displayed a transformed phenotype in vitro , and expressed mutant KRAS and TP53 ( 75 ). These transformed epithelial cells were injected into SCID mice and formed subcutaneous tumors that were histologically and phenotypically similar to human pancreatic ductal adenocarcinoma (PDAC) ( 75 ). In vivo injection of AdCre directly into the main pancreatic duct of an Oncopig resulted in several nodular tumors after 12 months.…”

Induction and characterization of pancreatic cancer in a transgenic pig model

“…VX2 tumors can be implanted in rabbit pancreas, and the GDA can be catheterized, but selective angiography of a pancreatic artery has not been reported in rabbits [35]. A previously reported Oncopig pancreatic cancer model used a surgical (not percutaneous) inoculation technique, and required 1 year for growth of small pancreatic tumors that were not visible on computed tomography [39]. The prior Oncopig paper also reported development of large tumors (described as leiomyosarcomas) 16 days after inoculation, but these tumors were not characterized radiographically.…”

Porcine pancreatic ductal epithelial cells transformed with KRASG12Dand SV40T are tumorigenic

“…In 2018, induction of autochthonous pancreatic tumor in one KRAS/p53 Oncopig was accomplished 98 by injection of adenovirus-expressing-Cre into the pancreatic duct, in order to minimize transformation of non-epithelial cells. At the 12-month time point in this single subject, pancreatic tumor was not evident radiographically nor grossly, but was visible after organ sectioning.…”