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Here, we investigated the release of miR-424 in circulating small EVs or exosomes from prostate cancer patients and assessed the functional implications in multiple experimental models. We found higher frequency of circulating miR-424 positive EVs in patients with metastatic prostate cancer compared to patients with primary tumors and BPH. Release of miR-424 in small EVs was enhanced in cell lines (LNCaP<jats:sup>abl<\/jats:sup>), transgenic mice (Pb-Cre4;Pten<jats:sup>flox\/flox<\/jats:sup>;Rosa26<jats:sup>ERG\/ERG<\/jats:sup>) and patient-derived xenograft (PDX) models of aggressive disease. EVs containing miR-424 promoted stem-like traits and tumor-initiating properties in normal prostate epithelial cells while enhanced tumorigenesis in transformed prostate epithelial cells. Intravenous administration of miR-424 positive EVs to mice, mimicking blood circulation, promoted miR-424 transfer and tumor growth in xenograft models. Circulating miR-424 positive EVs from patients with aggressive primary and metastatic tumors induced stem-like features when supplemented to prostate epithelial cells. This study establishes that EVs-mediated transfer of miR-424 across heterogeneous cell populations is an important mechanism of tumor self-sustenance, disease recurrence and progression. These findings might indicate novel approaches for the management and therapy of prostate cancer.<\/jats:p>","DOI":"10.1038\/s42003-020-01642-5","type":"journal-article","created":{"date-parts":[[2021,1,26]],"date-time":"2021-01-26T11:05:05Z","timestamp":1611659105000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Circulating extracellular vesicles release oncogenic miR-424 in experimental models and patients with aggressive prostate cancer"],"prefix":"10.1038","volume":"4","author":[{"given":"Domenico","family":"Albino","sequence":"first","affiliation":[]},{"given":"Martina","family":"Falcione","sequence":"additional","affiliation":[]},{"given":"Valeria","family":"Uboldi","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8470-0666","authenticated-orcid":false,"given":"Dada Oluwaseyi","family":"Temilola","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7294-3863","authenticated-orcid":false,"given":"Giada","family":"Sandrini","sequence":"additional","affiliation":[]},{"given":"Jessica","family":"Merulla","sequence":"additional","affiliation":[]},{"given":"Gianluca","family":"Civenni","sequence":"additional","affiliation":[]},{"given":"Aleksandra","family":"Kokanovic","sequence":"additional","affiliation":[]},{"given":"Alessandra","family":"St\u00fcrchler","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5113-3167","authenticated-orcid":false,"given":"Dheeraj","family":"Shinde","sequence":"additional","affiliation":[]},{"given":"Mariangela","family":"Garofalo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3123-3697","authenticated-orcid":false,"given":"Ricardo Pereira","family":"Mestre","sequence":"additional","affiliation":[]},{"given":"Vera","family":"Const\u00e2ncio","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0527-1750","authenticated-orcid":false,"given":"Martha","family":"Wium","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7884-7314","authenticated-orcid":false,"given":"Jacopo","family":"Burrello","sequence":"additional","affiliation":[]},{"given":"Nicol\u00f2","family":"Baranzini","sequence":"additional","affiliation":[]},{"given":"Annalisa","family":"Grimaldi","sequence":"additional","affiliation":[]},{"given":"Jean-Philippe","family":"Theurillat","sequence":"additional","affiliation":[]},{"given":"Daniela","family":"Bossi","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5827-0439","authenticated-orcid":false,"given":"Lucio","family":"Barile","sequence":"additional","affiliation":[]},{"given":"Rui M.","family":"Henrique","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-5345","authenticated-orcid":false,"given":"Carmen","family":"Jeronimo","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0736-9508","authenticated-orcid":false,"given":"Luiz Fernando","family":"Zerbini","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7079-557X","authenticated-orcid":false,"given":"Carlo V.","family":"Catapano","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4652-585X","authenticated-orcid":false,"given":"Giuseppina M.","family":"Carbone","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,1,26]]},"reference":[{"key":"1642_CR1","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1016\/S0140-6736(03)12713-4","volume":"361","author":"H Gronberg","year":"2003","unstructured":"Gronberg, H. 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