Carcinoma-associated fibroblast-derived lysyl oxidase-rich extracellular vesicles mediate collagen crosslinking and promote epithelial-mesenchymal transition via p-FAK/p-paxillin/YAP signaling.

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE
Xue Liu, Jiao Li, Xuesong Yang, Xiaojie Li, Jing Kong, Dongyuan Qi, Fuyin Zhang, Bo Sun, Yuehua Liu, Tingjiao Liu
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引用次数: 1

Abstract

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.

Abstract Image

癌相关成纤维细胞衍生的赖氨酸氧化酶丰富的细胞外囊泡介导胶原交联,并通过p-FAK/p-paxillin/YAP信号通路促进上皮-间质转化。
癌相关成纤维细胞(CAFs)是肿瘤微环境的主要细胞成分,通过修饰细胞外基质(ECM)促进癌症进展。肿瘤相关的ECM以赖氨酸氧化酶(LOX)催化的胶原交联为特征。小细胞外囊泡(sEVs)介导细胞间的通讯。然而,sev与ECM之间的相互作用仍不清楚。在这里,我们证明了从口腔鳞状细胞癌(OSCC)衍生的CAFs释放的sev诱导胶原交联,从而促进上皮-间质转化(EMT)。CAF sev最好与ECM结合,而不是被成纤维细胞吸收和诱导的胶原交联,LOX抑制剂或阻断抗体抑制了这种作用。活性LOX (αLOX)在CAF sev中富集,而不是LOX前体,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I型胶原的结合,阻断整合素α2β1通过干扰CAF sEV与I型胶原的结合抑制胶原交联。CAF sEV诱导的胶原交联通过FAK/paxillin/YAP通路促进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,提示了CAF诱导癌细胞EMT的关键机制。
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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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