Generation of pigs with a genetic predisposition to pancreatic cancer

• Applicants: Professorin Dr. Angelika Schnieke; Professor Dr. Eckhard Wolf
• Subject Area: Animal Breeding, Animal Nutrition, Animal Husbandry ; Evolutionary Cell and Developmental Biology (Zoology)
• Term: from 2009 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 147416069

Human pancreatic adenocarcinoma (PDAC) is a deadly disease that urgently requires methods of early diagnosis, and effective treatments. Representative animal models of the disease are important tools for the development and testing of such techniques. In mice, pancreas-specific expression of mutant Kras and Trp53 results in a phenotype that closely mimics PDAC, providing a model that is widely used for basic research. A similarly representative model of PDAC in pigs would significantly aid new diagnostic and therapeutic technology by bridging the gap between proof-of-concept studies in small animals and application in human patients. The aim of this project is to produce the genetically modified pigs necessary so this can be realised. This is a complex and ambitious undertaking that requires generating and testing a series of genetically engineered animals: 1, Animals with conditionally activatable mutations in the porcine KRAS and TP53 genes; 2, animals expressing Cre recombinase specifically in the pancreas and 3, dual reporter pigs to monitor the location of Cre activity. Most of this work has been accomplished in first funding period. In addition to the work originally specified, we carried out proof-of-principle studies showing that porcine mutations can be activated and lead to cellular transformation and tumorigenesis in a xenotransplantation model. We also present as yet unpublished data showing that inactivation of porcine TP53 leads to sarcoma, and mutation of porcine APC leads to colorectal adenocarcinoma. In both cases mimicking the human pathophenotype. Renewed funding is now required to complete work on the pancreatic cancer model. We will breed and analyse the required triple transgenic animals and characterise the disease phenotype. In parallel we will develop the tools necessary for in-depth study of PDAC and other cancers in pigs. This includes isolation and analysis of blood biomarkers particularly tumour specific exosomes, establishment of 2D and 3D porcine tumour cell culture and exome sequence analysis, which is not yet established for the pig. Exome analysis will have broad applicability for other researchers working with pigs, in both biomedicine and agriculture.

• DFG Programme: Research Grants