Extracellular Vesicles from Cancer-Associated Fibroblasts Containing Annexin A6 Induces FAK-YAP Activation by Stabilizing β1 Integrin, Enhancing Drug Resistance
Extracellular Vesicles from Cancer-Associated Fibroblasts Containing Annexin A6 Induces FAK-YAP Activation by Stabilizing β1 Integrin, Enhancing Drug Resistance
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DOI：
10.1158/0008-5472.can-19-3803
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发表时间：
2020-08-15
期刊：
影响因子：
11.2
通讯作者：
Ishimoto, Takatsugu
中科院分区：
文献类型：
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作者：
Uchihara, Tomoyuki;Miyake, Keisuke;Ishimoto, Takatsugu
肿瘤相关成纤维细胞(CAF)的胞外囊泡(EV)由多种有效载荷组成。尽管CAF影响胃癌细胞的侵袭特性，但CAF-EV在胃癌进展中的作用尚未阐明。在此，我们探讨了CAF-EV诱导胃癌细胞特性改变的分子机制。胃癌组织中CAF的表达与化疗后患者的预后不良有关。此外，CAF-EV可诱导胃癌细胞在细胞外基质(ECM)内形成肾小管网络并产生耐药性。对CAF-EV的蛋白质组学分析表明，Annexin A6通过激活β1整合素-粘着斑激酶(FAK-YAP)在ECM中胃癌细胞的网络形成和耐药中起关键作用。小鼠腹膜转移模型显示CAF-EV可诱导腹膜肿瘤耐药，抑制FAK或YAP在体内外均可有效减轻胃癌耐药。这些结果表明，Annexin A6在CAF-EV中具有耐药性，并通过抑制FAK-YAP信号与常规化疗相结合，为克服胃癌耐药提供了潜在的途径。意义：本研究阐明了一种新的分子机制，即CAF-EV中的Annexin A6通过稳定胃癌细胞表面的β1整合素来激活FAK-YAP，从而诱导耐药。
Extracellular vesicles (EV) from cancer-associated fibroblasts (CAF) are composed of diverse payloads. Although CAFs impact the aggressive characteristics of gastric cancer cells, the contribution of CAF-EV to gastric cancer progression has not been elucidated. Here, we investigated the molecular mechanism of the changes in gastric cancer characteristics induced by CAF-EV. CAF abundance in gastric cancer tissues was associated with poor prognosis of patients with gastric cancer receiving chemotherapy. Moreover, CAF-EV induced tubular network formation and drug resistance of gastric cancer cells in the extracellular matrix (ECM). Comprehensive proteomic analysis of CAF-EV identified that Annexin A6 plays a pivotal role in network formation and drug resistance of gastric cancer cells in the ECM via activation of beta 1 integrin-focal adhesion kinase (FAK)-YAP. A peritoneal metastasis mouse model revealed that CAF-EV induced drug resistance in peritoneal tumors, and inhibition of FAK or YAP efficiently attenuated gastric cancer drug resistance in vitro and in vivo. These findings demonstrate that drug resistance is conferred by Annexin A6 in CAF-EV and provide a potential avenue for overcoming gastric cancer drug resistance through the inhibition of FAK-YAP signaling in combination with conventional chemotherapeutics.Significance: This study elucidates a novel molecular mechanism through which Annexin A6 in CAF-EV activates FAK-YAP by stabilizing beta 1 integrin at the cell surface of gastric cancer cells and subsequently induces drug resistance.