循环肿瘤细胞时空异质性及其在肝癌转移复发中相关机制研究

项目名称： 循环肿瘤细胞时空异质性及其在肝癌转移复发中相关机制研究

项目编号： No.81472676

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 杨欣荣

作者单位： 复旦大学

项目金额： 75万元

中文摘要： 我们前期研究表明循环肿瘤细胞（Circulating tumor cell, CTC）数量与肝癌术后转移、复发关系密切，进一步研究提示CTC在肿瘤演进关键节点和转移关键部位CTC存在显著差异（即时空异质性）。目前CTC时空异质性在肝癌转移复发中的作用及分子机制不明。本课题在大量前期工作基础上：1）检测关键治疗节点和部位EpCAM+、CD133+、CD90+或CD24+ CTC亚群比例和分布情况，探讨其与肝癌疗效及预后的关系；2）利用单细胞RNA-Seq技术，比较CTC表达谱差异，绘制CTC特征性基因表达谱；3）基于CTC表达谱，筛选肝癌转移复发和耐药相关基因及通路并明确鉴定；4）验证决定CTC异质性的特征性表达谱和关键分子在肝癌转移复发预测和疗效监测中的作用。通过本研究进一步明确肝癌CTC的时空异质性，初步阐明其在转移复发和耐药中作用和机制，为临床提供新的肝癌转移复发预测和干预策略。

中文关键词： C09_肝和肝内胆管肿瘤；肝细胞癌；循环肿瘤细胞；时空异质性；转移/复发

英文摘要： We previously reported that circulating tumor cells (CTCs) were significantly correlated with postoperative recurrence and metastasis of hepatocellular carcinoma (HCC). Our recently research identified that the phenotype of CTC showed remarkable variation during tumor evolution and among different location of dissemination route(temporal and spatial heterogeneity). However, the clinical significance and underlying molecular mechanism of CTC's spatial and temporal heterogeneity is still unclear. In this study, we plan to (1) determine the distribution of EpCAM+, CD133+, CD90+, CD24+ CTC subsets in different vascular compartments and their dynamic changes during anti-HCC treatment, analyzing their relationship with clinical prognosis and treatment responsiveness. (2) Depict the expression profile of CTC using single-cell RNA-Seq technology in different vascular compartments and their dynamic changes during anti-HCC treatment; Develop a molecular characterization system of CTC that is highly correlated with CTC survival, HCC recurrence, organ specific metastasis and treatment responsiveness/resistance. (3) Investigate metastatsis/recurrence and drug resistance related key genes and signal pathways, revealing the underlying molecular mechanism. (4) Prospectively evaluate the clinical utility of CTC molecular characterization system in predicting postoperative recurrence/metastasis, and monitoring treatment efficacy in a real-time manner. In summary, the mechanism of CTC's spatial and temporal heterogeneity and its potential clinical significance are expectable from this project.

英文关键词： ;hepatocellular carcinoma;circulating tumor cell;the spatial and temporal heterogeneity;metastasis/recurrence