KRAS G12D and TP53 R167H Cooperate to Induce Pancreatic Ductal Adenocarcinoma in Sus scrofa Pigs

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....

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Bibliographic Details
Published in:Scientific reports 2018-08, Vol.8 (1), p.12548
Main Authors: Principe, Daniel R, Overgaard, Nana Haahr, Park, Alex J, Diaz, Andrew M, Torres, Carolina, McKinney, Ronald, Dorman, Matthew J, Castellanos, Karla, Schwind, Regina, Dawson, David W, Rana, Ajay, Maker, Ajay, Munshi, Hidayatullah G, Rund, Lauretta A, Grippo, Paul J, Schook, Lawrence B
Format: Article
Language:English
Subjects:
Adenocarcinoma - genetics
Adenocarcinoma - pathology
Animals
Animals, Genetically Modified
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - pathology
Female
Humans
Integrases
Mice, SCID
Mutation
Neoplasms, Experimental
Pancreatic Ducts - pathology
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - pathology
Proto-Oncogene Proteins p21(ras) - genetics
Sus scrofa - genetics
Tumor Microenvironment
Tumor Suppressor Protein p53 - genetics
Xenograft Model Antitumor Assays
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Summary: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-KRAS -TP53 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.
ISSN:2045-2322
DOI:10.1038/s41598-018-30916-6