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Osteopontin (OPN) is here identified as a ligand for ICOSL. OPN binds a different domain from that used by ICOS, and the binding induces a conformational change in OPN, exposing domains that are relevant for its functions. Here we show that in vitro, ICOSL triggering by OPN induces cell migration, while inhibiting anchorage-independent cell growth. The mouse 4T1 breast cancer model confirms these data. In vivo, OPN-triggering of ICOSL increases angiogenesis and tumor metastatization. The findings shed new light on ICOSL function and indicate that another partner beside ICOS may be involved; they also provide a rationale for developing alternative therapeutic approaches targeting this molecular trio.<\/jats:p>","DOI":"10.1038\/s42003-020-01333-1","type":"journal-article","created":{"date-parts":[[2020,10,26]],"date-time":"2020-10-26T11:03:40Z","timestamp":1603710220000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Osteopontin binds ICOSL promoting tumor metastasis"],"prefix":"10.1038","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3327-6305","authenticated-orcid":false,"given":"Davide","family":"Raineri","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2246-3183","authenticated-orcid":false,"given":"Chiara","family":"Dianzani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Cappellano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2789-799X","authenticated-orcid":false,"given":"Federica","family":"Maione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1370-9903","authenticated-orcid":false,"given":"Gianluca","family":"Baldanzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6210-5607","authenticated-orcid":false,"given":"Ilaria","family":"Iacobucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9860-0148","authenticated-orcid":false,"given":"Nausicaa","family":"Clemente","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Baldone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2700-3597","authenticated-orcid":false,"given":"Elena","family":"Boggio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3127-5686","authenticated-orcid":false,"given":"Casimiro L.","family":"Gigliotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renzo","family":"Boldorini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9032-0072","authenticated-orcid":false,"given":"Jos\u00e8 M.","family":"Rojo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7775-7154","authenticated-orcid":false,"given":"Maria","family":"Monti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Birolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6723-3931","authenticated-orcid":false,"given":"Umberto","family":"Dianzani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Chiocchetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,10,26]]},"reference":[{"key":"1333_CR1","doi-asserted-by":"publisher","first-page":"2863","DOI":"10.1002\/(SICI)1521-4141(199909)29:09<2863::AID-IMMU2863>3.0.CO;2-W","volume":"29","author":"D Buonfiglio","year":"1999","unstructured":"Buonfiglio, D. et al. 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E.B., U.D., and C.L.G. are founders of an UPO Spinoff (NOVAICOS). All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"615"}}