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In this study, the molecular composition of the tumor microenvironment of androgen-sensitive and castration-resistant metastatic prostate cancer is investigated by utilizing patient-derived xenograft models. Transcriptomic and histological analysis identify the presence of a pro-fibrotic stroma in the castration-resistant (LAPC9) versus the castration-sensitive (PNPCa, BM18) models, characterized by high levels of collagen and tenascin C deposition and upregulation of inflammatory markers. Intra-tumoral collagen- and tenascin-positive stromal areas specifically correlate with higher tumor invasiveness. Master regulator analysis identifies the transcription factor PU.1 as a mediator of the LAPC9 pro-fibrotic phenotype, whose transcriptional activity can be specifically inhibited by the small molecule DB1976. To test the effect of pharmacologic PU.1 inhibition a novel organoid-fibroblast 3D co-culture system, able to mimic features of the in vivo tumor microenvironment, is established. Inhibition of stromal PU.1 activity reverts the pro-fibrotic phenotype and, in turn, reduces tumor organoid growth. Besides identifying a novel molecular player of the pro-fibrotic stromal phenotype in prostate cancer, this study highlights the applicability of 3D tumor organoid-fibroblast co-cultures as in vitro tools to test the effect of stromal-targeting compounds.<\/jats:p>","DOI":"10.1038\/s42003-026-10297-7","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T17:34:57Z","timestamp":1780076097000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["PU.1 is a mediator of the reactive stromal response associated with castration-resistant prostate cancer"],"prefix":"10.1038","volume":"9","author":[{"given":"Francesco","family":"Bonollo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0665-8607","authenticated-orcid":false,"given":"Daniel","family":"Hanhart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"de Brot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanli","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1527-3151","authenticated-orcid":false,"given":"Panagiotis","family":"Chouvardas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beat","family":"Roth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George N.","family":"Thalmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9326-8177","authenticated-orcid":false,"given":"Natalie","family":"Sampson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6085-7706","authenticated-orcid":false,"given":"Marianna","family":"Kruithof-de Julio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1716-5237","authenticated-orcid":false,"given":"Sofia","family":"Karkampouna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,29]]},"reference":[{"key":"10297_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray, F. et al. 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