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Cancer\u2010associated fibroblasts (CAFs) are abundant components within the tumour microenvironment, playing critical roles in metastasis. Although increasing evidence supports a role for small extracellular vesicles (sEVs) in this process, their precise contribution and molecular mechanisms remain unclear, compromising the development of antimetastatic therapies. Here, we establish that CAF\u2010sEVs drive metastasis by mediating CAF\u2010cancer cell interaction and hyperactivating TGF\u2010\u03b2 signalling in tumour cells. Metastasis is abolished by genetically targeting CAF\u2010sEV secretion and consequent reduction of TGF\u2010\u03b2 signalling in cancer cells. Pharmacological treatment with dimethyl amiloride (DMA) decreases CAFs\u2019 sEV secretion, reduces TGF\u2010\u03b2 signalling levels in tumour cells and abrogates metastasis and tumour self\u2010seeding. This work defines a new mechanism required by CAFs to drive cancer progression, supporting the therapeutic targeting of EV trafficking to disable the driving forces of metastasis.<\/jats:p>","DOI":"10.1002\/jev2.70055","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T02:59:21Z","timestamp":1742180361000},"source":"Crossref","is-referenced-by-count":17,"title":["Extracellular Vesicles Secreted by Cancer\u2010Associated Fibroblasts Drive Non\u2010Invasive Cancer Cell Progression to Metastasis via TGF\u2010\u03b2 Signalling Hyperactivation"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7770-1778","authenticated-orcid":false,"given":"Adilson Fonseca","family":"Teixeira","sequence":"first","affiliation":[{"name":"Department of Surgery (The Royal Melbourne Hospital) The University of Melbourne  Parkville Victoria Australia"},{"name":"Huagene Institute, Kecheng Science and Technology Park  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Surgery (The Royal Melbourne Hospital) The University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josephine","family":"Iaria","sequence":"additional","affiliation":[{"name":"Department of Surgery (The Royal Melbourne Hospital) The University of Melbourne  Parkville Victoria Australia"},{"name":"Huagene Institute, Kecheng Science and Technology Park  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7234-342X","authenticated-orcid":false,"given":"Peter","family":"ten Dijke","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology, Oncode Institute Leiden University Medical Center  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong\u2010Jian","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Surgery (The Royal Melbourne Hospital) The University of Melbourne  Parkville Victoria Australia"},{"name":"Huagene Institute, Kecheng Science and Technology Park  Nanjing Jiangsu China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,16]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2020.06.081"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-013-1235-y"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00048.2019"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-0925"},{"issue":"2","key":"e_1_2_10_6_1","first-page":"457","article-title":"Membrane\u2010Associated Hsp72 From Tumor\u2010Derived Exosomes Mediates 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