肿瘤干细胞外泌体Tetraspanin分子调节腺癌转移机制研究

Exosomes derive from multiple cell types that are the key intercellular communicators and the pivotal elements of cancer metastasis. Tetraspanin is a family of four time transmembrane protein, which is enriched in exosomes. The molecular mechanism of cancer stem cell exosomal tetraspanin regulating adenocarcinoma metastasis and their components are poorly understood. The studies demonstrate that CD151 and Tspan8 mediate cancer metastasis by associating with impaired Integin and MMP molecules. In this study, we plan to explore, 1) the components of exosomes derived from adenocarcinoma cell and cancer stem cell and the impact on cancer metastasis; analysis the mechanism of cancer stem cell exosomal tetraspanin regulating cancer metastasis; 2) the cancer stem cell exosomal tetraspanin regulating metastasis in vivo by SCID and Knockout mice model; 3) the correlation of patient serum derived exosomal tetraspanin and cancer metastasis. The objectives of study aim to reveal the mechanism of exosomes regulating cancer metastasis, which improves the therapy and diagnosis for adenocarcinoma.

外泌体Exosomes由多种类型细胞分泌，是细胞间通讯交流的重要载体，肿瘤细胞外泌体是肿瘤转移的关键因子。Tetraspanin是一个四次跨膜蛋白家族，高丰度富集于外泌体中。肿瘤干细胞外泌体的组成及其Tetraspanin复合物在恶性腺癌转移机理尚不清楚。研究表明CD151和Tspan8与不同的Integin及MMP分子结合并调节肿瘤转移。本项目拟在此基础上，1）研究不同转移性的恶性腺癌细胞及肿瘤干细胞外泌体组分及其对肿瘤转移的影响；探索肿瘤干细胞外泌体Tetraspanin复合物调节肿瘤转移的机制。2）利用SCID小鼠及基因敲除小鼠模型验证肿瘤干细胞外泌体Tetraspanin复合物在体内调节肿瘤转移。3）分析临床标本及血清外泌体Tetraspanin复合物与肿瘤转移的相关性。阐明肿瘤干细胞外泌体调节肿瘤转移机制，为恶性腺癌的诊断治疗提供依据。

复发转移是胰腺癌及乳腺癌等腺癌难以治愈的关键，目前缺少关键的有效治疗诊断靶点。Tetraspanin是一个四次跨膜蛋白家族，高丰度富集于外泌体中。外泌体TSPAN8参与调控胰腺癌及乳腺癌转移的关键进程。我们前期研究表明CD151和TSPAN8与不同的Integin及MMP分子结合并调节肿瘤转移。本项目拟利用胰腺癌及乳腺癌来源外泌体，通过分析外泌体富集TSPAN8探索调控外泌体和靶细胞的结合的分子机制，分析外泌体富集TSPAN8对肿瘤细胞的转移相关表型的影响；进一步通过分析外泌体富集Tetraspanin分子CD82对肿瘤细胞黏附和迁移的调节，揭示CD82分子影响肿瘤转移的分子机制；通过测序分析胰腺癌来源外泌体富集miR-92a-3p并干扰肺组织内皮细胞DAB2IP和PTEN的表达，破坏细胞-细胞连接而影响肺组织中的血管屏障，而促进胰腺癌的肺转移。本研究明确外泌体富集TSPAN8和miR-92a-3p可以作为胰腺癌及乳腺癌复发转移治疗潜在靶点，为胰腺癌及乳腺癌复发转移提供新的科学依据。