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A paucity of pre-clinical models however has hampered functional studies of CAF heterogeneity. We demonstrate that our newly generated CAF biobank contains three FAP\n                    <jats:sup>+<\/jats:sup>\n                    -fibroblast subtypes, each with unique molecular and functional traits. Cultures with an early-activated phenotype expressed the highest levels of AR and exhibited AR-dependent growth, whereby AR inhibition suppressed their migration. Consistently, stromal cells expressing early-activation markers co-expressed nuclear AR in clinical specimens and were enriched in pre-neoplastic lesions\/low-grade PCa. Conversely, myofibroblastic CAF (myCAF) expressed low AR levels in vitro and in vivo\n                    <jats:italic>,<\/jats:italic>\n                    were insensitive at the proliferative and migratory levels to AR signaling modulation and significantly promoted PCa cell invasion in 3D composite collagen networks. Accordingly, myCAF constituted the predominant CAF subpopulation in stromogenic high-grade PCa and were enriched in aggressive disease states in PCa single cell atlases and castration-resistant LACP9 patient-derived xenografts. Exacerbation of the myCAF state upon castration of LAPC9-bearing hosts underscored these findings. Mechanistically, AR loss in myCAF was driven by an NF\u03baB-TGF\u03b21-YAP1 axis, whose combined pharmacological or genetic targeting synergistically repressed myofibroblastic hallmarks and impaired autophagic flux, effects that were potentiated by enzalutamide resulting in enhanced myCAF cell death. Collectively, data herein provide a mechanistic rationale for stromal AR loss in aggressive PCa and suggest that adjuvant targeting of the YAP1-TGF\u03b2 signaling axis may improve patient outcome.\n                  <\/jats:p>","DOI":"10.1186\/s13046-025-03578-2","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T08:55:28Z","timestamp":1764579328000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Unraveling the YAP1-TGF\u03b21 axis: a key driver of androgen receptor loss in prostate cancer-associated fibroblasts"],"prefix":"10.1186","volume":"45","author":[{"given":"Elena","family":"Brunner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Damisch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie Emma","family":"Groninger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Baschieri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Tyckaert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lukas","family":"Nommensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy","family":"Neumann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Fotakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zlatko","family":"Trajanoski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georg","family":"Sch\u00e4fer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Puhr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Heidegger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Ausserlechner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Ploner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Karkampouna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Bonollo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianna","family":"Kruithof-de Julio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Sampson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"issue":"6","key":"3578_CR1","doi-asserted-by":"publisher","first-page":"930","DOI":"10.1038\/s41416-022-02085-x","volume":"128","author":"F Pederzoli","year":"2023","unstructured":"Pederzoli F, Raffo M, Pakula H, Ravera F, Nuzzo PV, Loda M. 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PMID: 23824740; PMCID: PMC3745588.","DOI":"10.1158\/0008-5472.CAN-13-0023"}],"container-title":["Journal of Experimental &amp; Clinical Cancer Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-025-03578-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13046-025-03578-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13046-025-03578-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T14:12:58Z","timestamp":1781619178000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13046-025-03578-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,1]]},"references-count":107,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["3578"],"URL":"https:\/\/doi.org\/10.1186\/s13046-025-03578-2","relation":{},"ISSN":["1756-9966"],"issn-type":[{"value":"1756-9966","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,1]]},"assertion":[{"value":"11 May 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Prostate tissue samples were collected from consenting patients undergoing radical prostatectomy at the University Hospital of Innsbruck in accordance with the prior approval from the ethics committee of the Medical University of Innsbruck (UN4668 331\/4.12, 1129\/2022). Use of archived patient-derived FFPE samples was approved by the ethics committee of the Innsbruck Medical University (1072\/2018, UN4837, AM3174 including amendment 2). All patients gave written informed consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors have read and consent to this publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11"}}