Abstract PR03: The pig as a model for colorectal cancer

Abstract

Abstract Colorectal cancer is the fourth most common cancer worldwide with a mortality of more than 50%. Contrary to the increasing advances in cancer research colorectal cancer deaths are increasing in number. Most animal models also for colorectal cancer are in rodents. However, mice differ significantly in size, lifespan, physiology, anatomy and diet. Furthermore, genetically engineered mouse models for colorectal cancer show polyp development in the small intestine, contrary to the human phenotype that develops polyps in the large intestine. Therefore, a more suitable animal model is necessary. Pigs are increasingly recognized as a valuable model facilitating diagnostic and therapeutic strategies at human scale, longitudinal studies of disease initiation, progression and treatment response in preclinical trials. We generated gene targeted cloned pigs carrying the nonsense mutation, APC1311 that is orthologous to a human mutation associated with a very severe phenotype of colorectal cancer and the inherited condition familial adenomatous polyposis (FAP). In pigs the APC1311 mutation results in multiple adenomatous polyps in the colon and rectum that, so far, have progressed to carcinoma in situ. Histological and molecular analysis show that the porcine model recapitulates all major features of early stage human FAP. Breeding and analysis of the mutant pig herd has revealed segregation of traits that affect polyposis severity in animals carrying the same APC1311 mutation. We are currently investigating the genetic basis for this effect by comparing normal mucosa samples from low and high polyp animals and have discovered some genes that are differentially expressed. A progression study comparing low-grade with high-grade adenomas also identified differentially expressed genes and miRNAs. Further improvements of this model are targeted at generating organ/tissue specific Cre pigs to activate latent mutations such as KRAS and TP53 mutations in the colon. Additionally to encourage cancer progression we are working on the introduction of ubiquitous Cas9 expression in our APC1311 pigs to allow the activation of oncogenic pathways locally in vivo. Our porcine model provides a powerful new resource for preclinical cancer research, including identifying and investigating novel biomarkers for early detection. This abstract is also being presented as Poster A20. Citation Format: Carolin Wander, Tatiana Flisikowska, Krzysztof Flisikowski, Érica Schulze, Hans-Rudolf Fries, Stefan Bauersachs, Alexander Kind, Angelika Schnieke. The pig as a model for colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr PR03.