The interface of pancreatitis and early pancreatic cancer progression – In depth analysis of the novel, spontanous pancreatic cancer mouse model Cpa1 N256K – KC

• Applicant: Professor Dr. Jonas Rosendahl
• Subject Area: Gastroenterology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 504677297

Pancreatic cancer will be the second most common cause of death of all cancers in 2030. Amongst others chronic pancreatitis is a risk factor for the development of pancreatic cancer and the risk increase is highest in inherited chronic pancreatitis. In the last decades several genetic associations in chronic pancreatitis have been described for example with mutations in the cationic trypsinogen gene (PRSS1) or the serine protease inhibitor, Kazal type 1 (SPINK1). In 2013 a novel association with mutations in carboxypeptidase A1 (CPA1) with an early onset of the disease was reported. Recently, a novel animal model of chronic pancreatitis harbouring a knock in of the common p.N256K mutation was generated and presented with a spontaneous phenotype of chronic pancreatitis. This model is ideal to further elucidate the early mechanisms of inflammatory cues in carcinogenesis and for this purpose we crossbred Cpa1N256K with KrasG12D mutated mice (KC) to generate a novel model of pancreatic cancer development. In this model we will focus on early acinar events in vivo and in primary acinar cells as well as by overexpression of mutated CPA1 in murine pancreatic PanIN cells. The experiments will focus on events induced by endoplasmatic reticulum stress and on known pathways and immune phenotypes relevant for pancreatic cancer development on the level of the transcriptom and proteom. On the long-term identified pathways or immune phenotypes will be targeted to prevent the development of tumour stroma and tumour development.

• DFG Programme: Research Grants