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Modulation of the tumour microenvironment by extracellular vesicles (EVs) is known to facilitate the development of various cancers. The role of EVs in modulating the tumour microenvironment and their impact on the development of TSC tumours, however, remains unclear. This study, therefore, focuses on the poorly defined contribution of EVs to tumour growth in TSC. We characterised EVs secreted from <jats:italic>TSC2<\/jats:italic>\u2010deficient and <jats:italic>TSC2<\/jats:italic>\u2010expressing cells and identified a distinct protein cargo in <jats:italic>TSC2<\/jats:italic>\u2010deficient EVs, containing an enrichment of proteins thought to be involved in tumour\u2010supporting signalling pathways. We show EVs from <jats:italic>TSC2<\/jats:italic>\u2010deficient cells promote cell viability, proliferation and growth factor secretion from recipient fibroblasts within the tumour microenvironment. Rapalogs (mTORC1 inhibitors) are the current therapy for TSC tumours. Here, we demonstrate a previously unknown intercellular therapeutic effect of rapamycin in altering EV cargo and reducing capacity to promote cell proliferation in the tumour microenvironment. Furthermore, EV cargo proteins have the potential for clinical applications as TSC biomarkers, and we reveal three EV\u2010associated proteins that are elevated in plasma from TSC patients compared to healthy donor plasma.<\/jats:p>","DOI":"10.1002\/jev2.12336","type":"journal-article","created":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T00:24:24Z","timestamp":1687220664000},"source":"Crossref","is-referenced-by-count":10,"title":["Tuberous Sclerosis Complex cell\u2010derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3373-1064","authenticated-orcid":false,"given":"Muireann","family":"N\u00ed Bhaoighill","sequence":"first","affiliation":[{"name":"Tissue Microenvironment Group School of Medicine Cardiff University Cardiff UK"},{"name":"Division of Cancer and Genetics School of Medicine Cardiff University Cardiff UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3133-0670","authenticated-orcid":false,"given":"Juan M.","family":"Falc\u00f3n\u2010P\u00e9rez","sequence":"additional","affiliation":[{"name":"Exosomes Lab. 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