Department of Oral Pathology, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, China.
Int J Oral Sci. 2023 Aug 2;15(1):32. doi: 10.1038/s41368-023-00236-1.
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.
癌相关成纤维细胞（CAFs）是肿瘤微环境的主要细胞成分，通过改变细胞外基质（ECM）促进癌症进展。肿瘤相关 ECM 的特征是赖氨酰氧化酶（LOX）催化的胶原蛋白交联。小细胞外囊泡（sEVs）介导细胞间通讯。然而，sEVs 与 ECM 之间的相互作用仍不清楚。在这里，我们证明了口腔鳞状细胞癌（OSCC）衍生的 CAFs 释放的 sEVs 诱导胶原蛋白交联，从而促进上皮间质转化（EMT）。CAF sEVs 更倾向于与 ECM 结合，而不是被成纤维细胞摄取并诱导胶原蛋白交联，LOX 抑制剂或阻断抗体抑制了这种作用。活性 LOX（αLOX），而不是 LOX 前体，在 CAF sEV 中富集，并与 sEV 表面的骨膜蛋白、纤维连接蛋白和骨形态发生蛋白 1 相互作用。CAF sEV 相关整合素 α2β1 介导 CAF sEV 与胶原 I 的结合，阻断整合素 α2β1 通过干扰 CAF sEV 与胶原 I 的结合抑制胶原交联。CAF sEV 诱导的胶原蛋白交联通过 FAK/paxillin/YAP 通路促进 OSCC 的 EMT。总之，这些发现揭示了 CAF sEV 在肿瘤 ECM 重塑中的新作用，提示了 CAF 诱导癌细胞 EMT 的关键机制。
