Journal article
KRAS(G12D) and TP53(R167H) Cooperate to Induce Pancreatic Ductal Adenocarcinoma in Sus scrofa Pigs
University of Illinois at Chicago1
National Veterinary Institute, Technical University of Denmark2
T-cells & Cancer, Division of Immunology & Vaccinology, National Veterinary Institute, Technical University of Denmark3
California State University Los Angeles4
Illinois State University5
Northwestern University6
University of Illinois at Urbana-Champaign7
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(G12D)-TP53(R167H) 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.
Language: | English |
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Publisher: | Nature Publishing Group UK |
Year: | 2018 |
Pages: | 12548 |
ISSN: | 20452322 |
Types: | Journal article |
DOI: | 10.1038/s41598-018-30916-6 |
ORCIDs: | 0000-0002-2346-5949 , 0000-0003-0761-7196 and Overgaard, Nana Haahr |
Adenocarcinoma Animals Animals, Genetically Modified Carcinoma, Pancreatic Ductal Cre recombinase Female Humans Integrases KRAS protein, human Mice, SCID Mutation Neoplasms, Experimental Pancreatic Ducts Pancreatic Neoplasms Proto-Oncogene Proteins p21(ras) Sus scrofa TP53 protein, human Tumor Microenvironment Tumor Suppressor Protein p53 Xenograft Model Antitumor Assays