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

到2030年，胰腺癌将成为所有癌症的第二大死因。其中，慢性胰腺炎是胰腺癌发生的危险因素，遗传性慢性胰腺炎的风险增加最高。在过去的几十年里，已经描述了几种与慢性胰腺炎相关的基因，例如阳离子胰蛋白酶原基因(PRSS1)或丝氨酸蛋白酶抑制因子1(SPINK1)的突变。2013年，一个新的与羧基肽酶A1(CPA1)突变与疾病早期发病有关的报道被报道。最近，一种新的慢性胰腺炎动物模型被产生，该模型含有常见的p.N256K突变的敲击，并呈现出一种自发性的慢性胰腺炎表型。该模型是进一步阐明炎症信号在肿瘤发生中的早期机制的理想模型，为此，我们将Cpa1N256K与KrasG12D突变小鼠(KC)杂交，产生了一种新的胰腺癌发展模型。在这个模型中，我们将专注于体内和原代腺泡细胞中的早期腺泡事件，以及小鼠胰腺Panin细胞中突变的CPA1的过表达。这些实验将集中在内质网应激诱导的事件以及与胰腺癌发生相关的已知途径和免疫表型的转录和蛋白质组水平上。从长远来看，已确定的途径或免疫表型将被用于预防肿瘤间质的发展和肿瘤的发展。

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.