癌相关成纤维细胞（CAFs）是肿瘤微环境的主要细胞成份，通过改变细胞外基质（ECM）促进癌症进展。肿瘤相关的ECM特征是由赖氨酸氧化酶（LOX）催化的胶原交联。小型细胞外囊泡（sEVs）介导细胞间通讯。然而，sEVs与ECM之间的相互作用尚不清楚。在这里，我们证明了由口腔鳞状细胞癌（OSCC）来源的CAF释放的sEVs诱导胶原蛋白交联，从而促进上皮间质转变（EMT）。CAF sEVs优先与ECM结合，而不是被成纤维细胞摄取，并诱导胶原蛋白交联，而LOX抑制剂或阻断抗体抑制了这个效应。活性LOX（αLOX），而不是LOX前体，在CAF sEVs中富集，并与sEVs表面的骨桥蛋白、纤维连接蛋白和骨形态发生蛋白-1相互作用。CAF sEV相关的整合素α2β1介导CAF sEVs与胶原I的结合，并且阻断整合素α2β1通过干扰CAF sEV与胶原I的结合抑制了胶原蛋白交联。CAF sEV诱导的胶原蛋白交联通过FAK/paxillin/YAP途径促进了OSCC的EMT。综上所述，这些发现揭示了CAF sEV在肿瘤ECM重塑中的新作用，显示CAF诱导癌细胞EMT的关键机制。© 2023. 作者。

Carcinoma-associated fibroblasts (CAFs) are the main cellular components of the tumor microenvironment and promote cancer progression by modifying the extracellular matrix (ECM). The tumor-associated ECM is characterized by collagen crosslinking catalyzed by lysyl oxidase (LOX). Small extracellular vesicles (sEVs) mediate cell-cell communication. However, the interactions between sEVs and the ECM remain unclear. Here, we demonstrated that sEVs released from oral squamous cell carcinoma (OSCC)-derived CAFs induce collagen crosslinking, thereby promoting epithelial-mesenchymal transition (EMT). CAF sEVs preferably bound to the ECM rather than being taken up by fibroblasts and induced collagen crosslinking, and a LOX inhibitor or blocking antibody suppressed this effect. Active LOX (αLOX), but not the LOX precursor, was enriched in CAF sEVs and interacted with periostin, fibronectin, and bone morphogenetic protein-1 on the surface of sEVs. CAF sEV-associated integrin α2β1 mediated the binding of CAF sEVs to collagen I, and blocking integrin α2β1 inhibited collagen crosslinking by interfering with CAF sEV binding to collagen I. CAF sEV-induced collagen crosslinking promoted the EMT of OSCC through FAK/paxillin/YAP pathway. Taken together, these findings reveal a novel role of CAF sEVs in tumor ECM remodeling, suggesting a critical mechanism for CAF-induced EMT of cancer cells.© 2023. The Author(s).