Carcinoma-associated fibroblast-derived lysyl oxidase-rich extracellular vesicles mediate collagen crosslinking and promote epithelial-mesenchymal transition via p-FAK/p-paxillin/YAP signaling
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 extra...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-08-01
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| Series: | International Journal of Oral Science |
| Online Access: | https://doi.org/10.1038/s41368-023-00236-1 |
| _version_ | 1797752861348593664 |
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| author | Xue Liu Jiao Li Xuesong Yang Xiaojie Li Jing Kong Dongyuan Qi Fuyin Zhang Bo Sun Yuehua Liu Tingjiao Liu |
| author_facet | Xue Liu Jiao Li Xuesong Yang Xiaojie Li Jing Kong Dongyuan Qi Fuyin Zhang Bo Sun Yuehua Liu Tingjiao Liu |
| author_sort | Xue Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T17:09:35Z |
| format | Article |
| id | doaj.art-c26470b4f9ff46de99f1678475cb8447 |
| institution | Directory Open Access Journal |
| issn | 2049-3169 |
| language | English |
| last_indexed | 2024-03-12T17:09:35Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | International Journal of Oral Science |
| spelling | doaj.art-c26470b4f9ff46de99f1678475cb84472023-08-06T11:08:42ZengNature Publishing GroupInternational Journal of Oral Science2049-31692023-08-0115111510.1038/s41368-023-00236-1Carcinoma-associated fibroblast-derived lysyl oxidase-rich extracellular vesicles mediate collagen crosslinking and promote epithelial-mesenchymal transition via p-FAK/p-paxillin/YAP signalingXue Liu0Jiao Li1Xuesong Yang2Xiaojie Li3Jing Kong4Dongyuan Qi5Fuyin Zhang6Bo Sun7Yuehua Liu8Tingjiao Liu9Department of Oral Pathology, Shanghai Stomatological Hospital & School of Stomatology, Fudan UniversityDepartment of Oral Pathology, Shanghai Stomatological Hospital & School of Stomatology, Fudan UniversityDepartment of Biochemistry and Molecular Biology, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian Medical UniversitySchool of Stomatology, Dalian Medical UniversitySchool of Stomatology, Dalian Medical UniversityDepartment of Oral Surgery, the First Affiliated Hospital of Dalian Medical UniversityDepartment of Oral Surgery, the Second Affiliated Hospital of Dalian Medical UniversityDepartment of Oral Surgery, the Second Affiliated Hospital of Dalian Medical UniversityShanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan UniversityDepartment of Oral Pathology, Shanghai Stomatological Hospital & School of Stomatology, Fudan UniversityAbstract 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.https://doi.org/10.1038/s41368-023-00236-1 |
| spellingShingle | Xue Liu Jiao Li Xuesong Yang Xiaojie Li Jing Kong Dongyuan Qi Fuyin Zhang Bo Sun Yuehua Liu Tingjiao Liu Carcinoma-associated fibroblast-derived lysyl oxidase-rich extracellular vesicles mediate collagen crosslinking and promote epithelial-mesenchymal transition via p-FAK/p-paxillin/YAP signaling International Journal of Oral Science |
| title | Carcinoma-associated fibroblast-derived lysyl oxidase-rich extracellular vesicles mediate collagen crosslinking and promote epithelial-mesenchymal transition via p-FAK/p-paxillin/YAP signaling |
| title_full | Carcinoma-associated fibroblast-derived lysyl oxidase-rich extracellular vesicles mediate collagen crosslinking and promote epithelial-mesenchymal transition via p-FAK/p-paxillin/YAP signaling |
| title_fullStr | Carcinoma-associated fibroblast-derived lysyl oxidase-rich extracellular vesicles mediate collagen crosslinking and promote epithelial-mesenchymal transition via p-FAK/p-paxillin/YAP signaling |
| title_full_unstemmed | Carcinoma-associated fibroblast-derived lysyl oxidase-rich extracellular vesicles mediate collagen crosslinking and promote epithelial-mesenchymal transition via p-FAK/p-paxillin/YAP signaling |
| title_short | Carcinoma-associated fibroblast-derived lysyl oxidase-rich extracellular vesicles mediate collagen crosslinking and promote epithelial-mesenchymal transition via p-FAK/p-paxillin/YAP signaling |
| title_sort | carcinoma associated fibroblast derived lysyl oxidase rich extracellular vesicles mediate collagen crosslinking and promote epithelial mesenchymal transition via p fak p paxillin yap signaling |
| url | https://doi.org/10.1038/s41368-023-00236-1 |
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