Deciphering the interaction of genetic and non-genetic factors in the development of pancreatic cancer: the Ctrb1Δex6 mouse model as a discovery tool

• Applicant: Dr. Sarah Klauß
• Subject Area: Gastroenterology ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545419946

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, causing nearly as many deaths as cases due to its typically late-stage diagnosis and limited treatment effectiveness. The main aim of the proposed research project is to gain a deeper insight into the molecular pathology of pancreatic cancer and how it is influenced by genetic and non-genetic risk factors, thereby enabling the development of tools for early detection and prevention strategies. Genome-wide association studies (GWAS) have identified a variant in the CTRB2 gene (CTRB2 exon6 deletion) that is common in the general population and is associated with an increased risk of PDAC. It is suspected that this low-penetrance variant represents a genetic susceptibility to PDAC. The extent to which the PDAC risk of this variant is modified by non-genetic risk factors such as diabetes, obesity and chronic pancreatitis, and whether the interplay with other genetic variants plays a role, remains poorly understood. The host, Francisco X. Real, has developed a genetic mouse model (Ctrb1Δex6) that mimics the human CTRB2 exon6 deletion. Since PDAC is initiated by a kras mutation in 90% of cases, we first plan to characterize Ctrb1Δex6 mice that additionally carry a mutant kras allele and to investigate the occurrence of tumor lesions over time. We will further investigate the influence of the two non-genetic risk factors obesity and chronic pancreatitis on the development of PDAC in both mouse strains. For this purpose, in one experiment the mice will be put on a high-fat diet and in another one, experimental chronic pancreatitis will be induced by the established caerulein model. At different time points, tumor development, inflammation, endoplasmic reticulum stress (ER stress) and diabetes development will be assessed. In addition, we plan to use transcriptome data and clinical data from two large case-control studies, the PanGenEU and UKBiobank studies, to further investigate the variant in a clinical context and validate the experimental results. We will analyze the interaction of the CTRB2 exon6 deletion with other genes harboring PDAC-associated GWAS-hits in the different cohorts. We also want to analyze the role of risk factors, such as diabetes, age, smoking and many others, in this process and to investigate how they influence, together with the genetic variants, the risk of developing PDAC. The goal is to uncover potential mechanistic pathways that underlie the association between relevant risk factors of PDAC and its subtypes.

• DFG Programme: WBP Fellowship
• International Connection: Spain
• Host: Nuria Malats, Ph.D.