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To identify EV\u2010bound proteins related to metastasis, we used mass spectrometry to profile EVs from highly and poorly metastatic breast cancer lines of human and mouse origins. Comparative mass spectrometry indicated that integrins, including \u03b1v and \u03b21 subunits, are preferentially enriched in EVs of highly metastatic origin over those of poorly metastatic origin. These results are consistent with our histopathological findings, which show that integrin \u03b1v is associated with disease progression in breast cancer patients. Integrin \u03b1v colocalizes with the multivesicular\u2010body marker CD63 at a higher frequency in the tumour and is enriched in circulating EVs of breast cancer patients at late stages when compared with circulating EVs from early\u2010stage patients. With a magnetic bead\u2010based flow cytometry assay, we confirmed that integrins \u03b1v and \u03b21 are enriched in the CD63<jats:sup>+<\/jats:sup> subsets of EVs from both human and mouse highly metastatic cells. By analysing the level of integrin \u03b1v on circulating EVs, this assay could predict the metastatic potential of a xenografted mouse model. To explore the export mechanism of integrins into EVs, we performed immunoprecipitation mass spectrometry and identified members of the galectin family as potential shuttlers of integrin \u03b1v\u03b21 into EVs. In particular, knockdown of galectin\u20103, but not galectin\u20101, causes a reduction in the levels of cell surface integrins \u03b21 and \u03b1v, and decreases the colocalization of these integrins with CD63. Importantly, knockdown of galectin\u20103 leads to a decrease of integrin \u03b1v\u03b21 export into the EVs concomitant with a decrease in the metastatic potential of breast cancer cells. Moreover, inhibition of the integrin \u03b1v\u03b21 complex leads to a reduction in the binding of EVs to fibronectin, suggesting that integrin \u03b1v\u03b21 is important for EV retention in the extracellular matrix. EVs retained in the extracellular matrix are taken up by fibroblasts, which differentiate into cancer associated fibroblasts. In summary, our data indicate an important link between EV\u2010bound integrin \u03b1v\u03b21 with breast cancer metastasis and provide additional insights into the export of integrin \u03b1v\u03b21 into EVs in the context of metastasis.<\/jats:p>","DOI":"10.1002\/jev2.12234","type":"journal-article","created":{"date-parts":[[2022,8,4]],"date-time":"2022-08-04T01:39:15Z","timestamp":1659577155000},"source":"Crossref","is-referenced-by-count":49,"title":["\u03b1v\u03b21 integrin is enriched in extracellular vesicles of metastatic breast cancer cells: A mechanism mediated by galectin\u20103"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8561-6928","authenticated-orcid":false,"given":"Daniel Xin","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Institute for Digital Medicine Yong Loo Lin School of Medicine National University of Singapore  Queenstown Singapore"},{"name":"Department of Surgery Cancer Program, Immunology Program and Nanomedicine Translational Research Program Yong Loo Lin School of Medicine National University of Singapore  Queenstown Singapore"},{"name":"Department of Biomedical Sciences Jocky Club College of Veterinary Medicine and Life Sciences City University of Hong Kong  Kowloon Hong Kong SAR"},{"name":"Department of Molecular Biology and Genetics Cornell University  Ithaca New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5933-3502","authenticated-orcid":false,"given":"Xuan T. 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