耐药细胞源性外泌体EphA2介导癌细胞间通讯促进乳腺癌转移的分子机制研究

耐药和转移是导致癌症患者治疗失败和死亡的主要原因。肿瘤获得耐药能力的同时常伴随着侵袭转移能力的增强，但分子机制不明。前期研究发现乳腺癌耐药细胞能够通过外泌体增强敏感细胞的侵袭能力，同时细胞发生类EMT改变。基于蛋白质组学技术结合细胞学实验证实外泌体EphA2介导了这种作用。传统观点认为EphA2和配体Ephrin A1介导的信号传导需要细胞间直接接触，而外泌体EphA2则是一种新型非依赖于细胞间直接接触的信号途径，其作用机制尚不明确。转录组学分析发现富含EphA2的外泌体作用后细胞中上调的基因在EMT相关的TGFβ通路和粘附相关通路发生富集，继而证实耐药细胞源性外泌体EphA2通过调控药物敏感细胞发生EMT进而促进侵袭转移。本研究拟利用不同EphA2表达水平和活性状态的外泌体，结合多种研究手段阐明外泌体EphA2介导的正、反向信号通路在细胞间通讯中的功能和促进乳腺癌细胞侵袭转移的详细机制。

Drug resistance and metastasis are the leading causes of treatment failure and death in cancer patients. Acquirement of drug resistance by cancer cells is often accompanied by an increased ability to invade and metastasize. However, the detailed mechanism remains unclear. Previous studies have shown that drug-resistant breast cancer cell-derived exosomes promote the invasion of sensitive cells by inducing EMT-like changes. Proteomic profiling of exosomes and subsequent in vitro cell invasion assays confirmed that the exosomal EphA2 mediates the pro-invasive effect. Traditionally, it is thought that the direct cell–cell contact is required for EphA2 and Ephrin A1 signaling. While EphA2 anchored in exosomes represents a novel type of intercellular communication that does not rely on direct cell–cell contact, and its mechanism remains largely unknown. Transcriptomics analysis found that the up-regulated gene sets in EphA2-rich exosomes treated cells were enriched in EMT-related TGFβ pathways and ECM-adhesion signaling pathways. Therefore, these data suggest that drug-resistant cell-derived exosomal EphA2 promotes the invasion and metastasis of breast cancer cells by inducing EMT. In this study, we intend to use exosomes with distinct expression levels of EphA2 or its mutants in combination with multiple research methods to elucidate the function of exosomal EphA2-mediated forward and reverse signaling pathways in intercellular communication and the detailed mechanism to promote breast cancer cell invasion and metastasis.