肺癌细胞来源的外泌体中烯醇化酶（Enolases）参与代谢重编程和恶性侵袭的机制研究

Lung cancer is the leading cause of morbidity and mortality worldwide, among all kinds of cancer. In China, approximately 610,000 cancer deaths were due to lung cancer in 2015. For the reason of high mortality, lung cancer are hard to discover and diagnose in an early stages, and in late stages it tend to be high metastasis and drug resistance. In this proposal, we plan to design the experiment through two aspects, clinical detection and molecular mechanism. First, exosomes were isolated from plasma of SCLC (small cell lung cancer), NSCLC (non-small cell lung cancer) and control cohorts, following with proteomic analysis of subtyping enolases and correlation analysis between enolase subtype/amount in exosome and survival time after treatment. Then, we plan to figure out molecular mechanisms of enolase through enhancing glycolysis, promoting extracellular matrix reconstruction and initiating “pre-metastatic niches”, by means of co-culture of exosome with lung tissue or tumor cells (in vitro) and exosome injection into tumor-bearing mice (in vivo). Therefore, the study of exosomal enolase in lung cancer early diagnosis, tumor invasion and metastasis mechanism, may provide a promising tool for early diagnosis, disease process monitoring, drug efficacy/ responsiveness monitoring, individualized treatment planning and prognostic evaluation.

肺癌是世界范围内发病率和死亡率最高的恶性肿瘤，我国仅2015年就有约61万人死于肺癌。肺癌之所以死亡率高，不仅因为早期发现和诊断比较难，还由于晚期肺癌容易转移和耐药。本项目旨在从临床研究和分子机制两方面入手，首先通过分离小细胞肺癌、非小细胞肺癌和对照人群的血浆外泌体，进行蛋白质组学分析，再针对烯醇化酶进行精细分型并分析其与治疗后生存期的相关关系。然后，将癌细胞来源的外泌体与肺组织或肿瘤细胞共培养（体外试验），同时利用荷瘤小鼠尾静脉注射外泌体等手段（体内试验），从①增强糖酵解、②促进胞外基质重构 和 ③促“前转移占位形成”三个角度，探讨外泌体中烯醇化酶促进癌细胞代谢重编程、恶性侵袭和迁移的分子机制。总之，开展肺癌外泌体中烯醇化酶在早期诊断及肿瘤恶性侵袭和转移机制的研究，对建立早期诊断方法、疾病进程监测、药物疗效/反应性监测、个体化治疗方案确定和肺癌治疗的预后评估等，具有十分重要的意义。