Widely-used genetically modified mice have revolutionized the field of cancer research by providing reliable in vivo systems with similar, if not identical, molecular alterations. Furthermore, Cre/Lox technology has afforded greater tissue specificity, with many of the developing cancer phenotypes recapitulating those observed in humans. However, despite these strengths, there are a number of notable limitations when comparing mice to humans including small sample sizes, dramatic differences in physiology, and often dissimilar drug responses. Pig models would alleviate these shortcomings if they were to have a repertoire of gene signatures observed in human cancer, like those engineered in mice. Therefore, to achieve this goal, we have engineered a pig model with the Cre-responsive transgene encoding KRASG12D and TP53R167H. Hence, tissue-specific targeted Cre would generate simultaneous expression of mutant KRAS and p53 alleles to induce cellular changes leading to cancer. Pig pancreases were injected with adenovirus containing a cre expression vector (adenoCre) in an attempt to generate a model of pancreatic cancer. Initial injections of adenoCre into the parenchymal body of the pancreas led to the development of acinar-ductal metaplasia (ADM), though the clear predominant histotype was leiomyosarcoma immediately adjacent to the pancreas. Pancreatic ADM was characterized by concomitant localization of amylase (acinar cell marker) and CK19 (ductal cell marker) in the same pancreatic acinus, with an occasional few cells expressing both cell markers. These lesions were further characterized and exhibited increased proliferation via PCNA staining , as well the development of surrounding desmoplastic stroma (enhanced trichrome, vimentin, and aSMA staining; a marker of pancreatic stellate cells) with a robust inflammatory component (strong CD11b and CAE staining). Based on the lack of pancreas specificity, the experiment was repeated by injecting adenoCre into the main pancreatic duct. This 10-month-old pig appears relatively healthy after, which was expected considering this was a fully adult pig prior to manipulation. We will fully access this pig in 2 months to determine if strict pancreatic duct injection of adenoCre induces ADM, neoplastic disease, and/or ductal adenocarcinoma. Based on these encouraging findings, we anticipate having a robust model of pancreatic cancer in the pig, and plan to extend this study to generate models of other solid tumors with high rates of KRAS and p53 mutations. These porcine models may significantly impact preclinical studies, as diseases induced in pigs are likely more physiologically relevant to those in humans, with a potentially similar pharmacokinetic profile following drug treatment. Indeed, due to the size of the organs and volume of blood, samples can be more readily shared among multiple groups of investigators facilitating greater collaboration and expanding future research.
American Association for Cancer Research Annual Meeting, April 16-20, 2016, New Orleans, LA