多杀性巴氏杆菌及其外毒素PMT调控胰腺导管腺癌发生发展的机制研究

人体组织微生物是肿瘤微环境的重要组成，与肿瘤发生发展关系密切，但胰腺组织微生物及其代谢物对胰腺肿瘤的影响尚未阐明。前期我们通过多研究大数据整合分析发现胰腺导管腺癌组织内存在复杂的微生物成分,且在癌及癌旁组织中有显著差异；并初步鉴定出多杀性巴氏杆菌(Pm)等差异微生物，且Pm在癌组织中的丰度显著增加。文献显示Pm可分泌多杀性巴氏杆菌毒素(PMT)来促进宿主细胞增殖和凋亡抵抗等，并可通过PLCβ/PKC等通路发挥潜在促癌作用。本项目拟在前期大数据分析的基础上，利用临床样本、体外细胞模型和荷瘤动物体内模型，在组织水平和细胞水平系统验证胰腺组织内Pm与胰腺导管腺癌发生发展的相关性，并利用PMT失活突变体等探究PMT在Pm调控PLCβ/PKC通路活化和肿瘤生物学特性中的作用与机制,从而揭示胰腺组织微生物参与肿瘤发生发展的新机制，并为胰腺癌诊疗新技术研究提供候选靶标。

Human tissue microbiota is an important component of tumor microenvironment, and is closely related to the oncogenesis and progression of tumor. However, the effects of pancreatic tissue microbiota and its metabolites on pancreatic ductal adenocarcinoma has not been clarified. In our previous study, we found that there was complex microbial composition through multi-study big-data integration analysis, and there were significant differences in microbial composition between the carcinoma and adjacent normal tissues. A set of differentially distributed microbes, including Pasteurella multocida (Pm), were identified, and the abundance of Pm was found to increase significantly in tumor tissue. Literature retrieval results show that Pm can secret the exotoxin, Pasteurella multocida toxin (PMT), to promote the proliferation and apoptotic resistance of host cells, and plays a potential role in carcinogenesis through PLCβ/PKC pathway. Therefore, based on our previous studies, this project intends to use clinical samples, in vitro cell model and tumor-burdened animal model to explore the associations between Pm and pancreatic ductal adenocarcinoma in tissue and cell level. The PMT and its deactivation mutant will be used to explore the roles and mechanisms of Pm and PMT regulating PLCβ/PKC pathway to activate the tumor biological activities. This project will reveal a new mechanism by which pancreatic tissue microbiota participates in the process of tumor oncogenesis and progression, and provide a candidate target for subsequent diagnosis and treatment studies on pancreatic ductal adenocarcinoma.