PRSS1 Mutation and Pancreatic Cancer Tumorigenesis

摘要： 胰腺导管腺癌(PDA)患者的5年相对生存率仅为8%。PDA是 预计到2030年将成为美国癌症相关死亡的第二大原因。了解关键所在 肿瘤发生的信号机制对于开发挽救生命的干预措施至关重要。遗传性 胰腺炎(HP)是一种常染色体显性遗传病，反复发作的急性胰腺炎(AP) 最终发展为慢性胰腺炎(CP)，到年龄时患胰腺癌的累积风险为44% 70年了。阳离子胰蛋白酶原基因(或PRSS1)突变是幽门螺杆菌最常见的致病因素。不幸的是， 针对幽门螺杆菌的有针对性的预防或治疗干预措施的发展受到了我们在 对其病理生理学的了解，这主要是由于从其获取组织的实际困难 人类胰腺在疾病的早期阶段，以及缺乏概括人类形态的动物模型 这种疾病。最近，我们开发了一种新的幽门螺杆菌模型，通过表达人类常见的突变体 PRSS1(PRSS1R122H)在小鼠(J Clin Invest.2020年1月2日；130(1)：189-202)。突变体的转基因表达 PRSS1可引起重症急性胰腺炎，发展为慢性胰腺炎、癌前病变和胰腺癌。这 惠普的模型将为我们提供一个强大的工具来实现我们理解启蒙的长期目标 幽门螺杆菌的事件，并制定具体的策略，以防止其进展为胰腺癌。在这 提案，我们将使用我们独特的人源化胰腺炎模型来测试我们的中心假设，即病因 腺泡内应激与PRSS1基因突变共同导致胰腺肿瘤的发生 信号通路与胰酶受体介导的持续炎症环境。我们将描述这些特性 新开发的幽门螺杆菌模型中的信号通路及其在胰腺癌中的作用 通过药理学和遗传学两种方法的肿瘤发生。我们预计这些研究将极大地 提高我们对幽门螺杆菌的发病机制及其进展到胰腺癌的认识，并提供新的 对开发/测试新的预防和治疗干预措施的见解。

Abstract: The 5-year relative survival of pancreatic ductal adenocarcinoma (PDA) patients is only 8%. PDA is predicted to be the second-leading cause of cancer related death in the U.S. by 2030. Understanding the key signaling mechanisms of tumorigenesis is critical for developing life-saving interventions. Hereditary pancreatitis (HP), an autosomal-dominant disorder with recurrent episodes of acute pancreatitis (AP) which eventually develops into chronic pancreatitis (CP), has a cumulative risk of pancreatic cancer of 44% by age 70 years. Cationic trypsinogen gene (or PRSS1) mutations are the most common causes of HP. Unfortunately, the development of targeted preventive or therapeutic interventions for HP has been hampered by gaps in our understanding of its pathophysiology, which is mainly due to the practical difficulties in obtaining tissues from human pancreas at early stages of the disease and the lack of animal models that recapitulate the human form of this disease. Recently we have developed a novel model of HP by expressing a common mutant of human PRSS1 (PRSS1R122H) in mice (J Clin Invest. 2020 Jan 2;130(1):189-202). Transgenic expression of mutant PRSS1 caused severe AP which progresses to CP, precancerous PanIN lesions, and pancreatic cancer. This model of HP will provide us with a powerful tool to fulfill our long-term goal of understanding the initiating events of HP and developing specific strategies to prevent its progression to pancreatic cancer. In this proposal, we will use our unique humanized pancreatitis model to test our central hypothesis that etiological factors and PRSS1 gene mutation cooperatively cause pancreatic tumorigenesis by intra-acinar cell stress signaling pathways and a trypsin receptor-mediated constant inflammatory milieu. We will characterize these signaling pathways in this newly developed HP model and investigate their roles in pancreatic cancer tumorigenesis by both pharmacological and genetic approaches. We expect these studies will significantly improve our understanding of the pathogenesis of HP, its progression to pancreatic cancer, and provide new insights for developing/testing novel preventive and therapeutic interventions.