胰腺癌对放化疗短期内即出现抵抗，其主要原因是放化疗后肿瘤再增殖，但具体机制不明。既往研究证实放化疗后濒死细胞中有多种Caspase活化，其中Caspase3可通过前列腺素E2促进肿瘤再增殖。申请人预实验首次发现：放化疗后濒死细胞中活化的Caspase3/1可分别促进LPA/IL-1释放；而LPA、IL-1分别与残留的存活肿瘤细胞中Hippo通路形成正反馈环路，促进肿瘤再增殖。本课题拟围绕“濒死细胞(Caspases)/残存细胞（Hippo）/肿瘤再增殖”这一主线，通过构建肿瘤再增殖体内外模型，采用显性负性突变体、shRNA等干预Caspases及Hippo通路活性，生物活体成像等技术评估再增殖情况，阐明放化疗后濒死细胞通过释放LPA/IL-1促进肿瘤再增殖的机制，并初步探究阻断肿瘤再增殖改善放化疗疗效的可行性。本项目将进一步解析肿瘤放化疗抵抗的机制，据此研发药物有望改善胰腺癌放化疗疗效。

Pancreatic cancer appears resistance to radiotherapy and chemotherapy in a short time, the main reason is tumor repopulation after radiotherapy and chemotherapy, but the specific mechanism is unknown. Previous studies have shown that there are many kinds of Caspases activation in dying cells after radiotherapy and chemotherapy, in which Caspase3 can promote tumor repopulation through stimulating prostaglandin E-2. In the pre-experiment, the applicant found for the first time that activated Caspase3/1 in dying cells after radiotherapy and chemotherapy could promote the release of LPA/IL-1, while LPA and IL-1 formed a positive feedback loop with Hippo pathway in residual surviving tumor cells, which promoted tumor repopulaiton. Based on the main line of "dying cells (Caspases) / residual cells (Hippo) / tumor repopulation", we constructed a tumor regeneration model in vitro and in vivo, and used dominant negative mutants, shRNA, and others to interfere the activity of Caspases and Hippo pathway. Biological maging and other techniques were used to evaluate the repopulation of residual surviving tumor cells after radiotherapy and chemotherapy. This project will clarify the mechanism of LPA/IL-1 release to promote tumor proliferation, and explore the feasibility of blocking the proliferation of tumor to improve the efficacy of radiotherapy and chemotherapy. This project will further explore the mechanism of radiotherapy and chemotherapy resistance in pancreatic cancer, based on which, the development of drugs may improve the efficacy of radiotherapy and chemotherapy in pancreatic cancer.