Cancer-associated myofibroblasts (mCAFs) represent a significant component of the tumor microenvironment due to their contributions to extracellular matrix (ECM) remodeling. The pro-tumor mechanisms of extracellular vesicles (EVs) by regulating mCAFs and related collagens remain poorly understood in oral squamous cell carcinoma (OSCC). In this study, through analysis of single-cell sequencing data and immunofluorescence staining, we confirmed the increased presence of mCAFs and enrichment of specific collagen types in OSCC tissues. Furthermore, we demonstrated that OSCC-derived EVs promote the transformation of fibroblasts into mCAFs, leading to tumor invasion. Proteomic analysis identified the presence of TGF-β1 in EVs and revealed its role in inducing mCAFs via the TGF-β1/SMAD signaling pathway. Experiments in vivo confirmed that EVs, particularly those carrying TGF-β1, trigger COL18high COL5high matrix deposition, thereby forming the pro-tumor ECM in OSCC. In summary, our investigation unveils the significant involvement of OSCC-derived EVs in orchestrating the differentiation of fibroblasts into mCAFs and modulating specific collagen types within the ECM. Therefore, this study provides a theoretical basis for targeting the EV-mediated TGF-β1 signaling pathway as a potential therapeutic strategy for OSCC.

中文翻译：

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OSCC 衍生的 EV 教育成纤维细胞并重塑胶原蛋白景观


癌症相关肌成纤维细胞 （mCAF） 是肿瘤微环境的重要组成部分，因为它们有助于细胞外基质 （ECM） 重塑。在口腔鳞状细胞癌 （OSCC） 中，细胞外囊泡 （EV） 通过调节 mCAFs 和相关胶原蛋白的促肿瘤机制仍然知之甚少。在这项研究中，通过分析单细胞测序数据和免疫荧光染色，我们证实了 OSCC 组织中 mCAFs 的存在增加和特定胶原蛋白类型的富集。此外，我们证明 OSCC 衍生的 EV 促进成纤维细胞转化为 mCAFs，导致肿瘤侵袭。蛋白质组学分析确定了 EV 中 TGF-β 1 的存在，并揭示了其在通过 TGF-β1/SMAD 信号通路诱导 mCAF 中的作用。体内实验证实，EV，尤其是携带 TGF-β1 的 EV，会触发 COL18high COL5high 基质沉积，从而在 OSCC 中形成促肿瘤 ECM。总之，我们的研究揭示了 OSCC 衍生的 EV 在协调成纤维细胞分化为 mCAF 和调节 ECM 内的特定胶原蛋白类型方面的重要参与。因此，本研究为靶向 EV 介导的 TGF-β1 信号通路作为 OSCC 的潜在治疗策略提供了理论基础。