{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE296nnn/GSE296466/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":[" Other","Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE296466"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"PU.1 is a mediator of the reactive stroma response associated with castration-resistant prostate cancer","description":"Emerging evidence demonstrates the pivotal role played by the tumor microenvironment, particularly cancer-associated fibroblasts, during prostate cancer tumorigenesis and the development of castration-resistant prostate cancer. In this study, we aimed to characterize the stromal gene expression profile of advanced stages of prostate cancer to identify targetable factors associated with castration-resistant prostate cancer progression. Transcriptomic and histological analysis of the mouse stromal component of androgen-sensitive (PNPCa, BM18) and castration-resistant (LAPC9) patient-derived xenograft models representative of advanced prostate cancer was performed. Master regulator analysis of the patient-derived xenograft stromal gene expression profile was performed to identify targetable stromal-associated transcription factors. Patient-derived xenograft collagen-based organoid tumor-fibroblast 3D co-cultures were established to study tumor-fibroblast interactions and to test the effect of an identified fibroblast-targeting compound. Transcriptomic and histological analysis determined the presence of a “reactive” pro-fibrotic stroma in the castration-resistant (LAPC9) versus the castration-sensitive (PNPCa, BM18) xenograft models, characterized by alpha-smooth muscle actin-positive “myofibroblast-like” cancer-associated fibroblasts, high levels of collagen and tenascin C deposition, and upregulation of myofibroblast and inflammatory markers. Intra-tumoral collagen- and tenascin-positive stromal areas specifically correlate with higher tumor invasiveness. Master regulator analysis identified the transcription factor PU.1 as a mediator of the LAPC9 pro-fibrotic phenotype, whose transcriptional activity can be specifically inhibited by a small molecule (DB1976) that prevents its DNA binding. In LAPC9 collagen-based tumor-fibroblast 3D co-cultures, inhibition of stromal PU.1 activity reverted the fibroblast-associated myofibroblast phenotype and, in turn, reduced tumor organoid growth. In this study, we identified the transcription factor PU.1 as a novel targetable molecular player of the pro-fibrotic, cancer-associated fibroblast phenotype in PCa, and we highlighted the applicability of 3D tumor organoid-fibroblast co-cultures as in vitro tools to test the effect of stromal-targeting compounds.","dates":{"publication":"2026/04/27"},"accession":"GSE296466","cross_references":{"GSM":["GSM8970859","GSM8970858","GSM8970860","GSM8970882","GSM8970881","GSM8970880","GSM8970846","GSM8970868","GSM8970867","GSM8970845","GSM8970866","GSM8970844","GSM8970843","GSM8970887","GSM8970865","GSM8970886","GSM8970864","GSM8970842","GSM8970863","GSM8970885","GSM8970884","GSM8970862","GSM8970883","GSM8970861","GSM8970849","GSM8970848","GSM8970869","GSM8970847","GSM8970871","GSM8970870","GSM8970857","GSM8970879","GSM8970878","GSM8970856","GSM8970877","GSM8970855","GSM8970854","GSM8970876","GSM8970875","GSM8970853","GSM8970874","GSM8970852","GSM8970873","GSM8970851","GSM8970872","GSM8970850"],"GPL":["24247"],"GSE":["296466"],"taxon":["Mus musculus"]}}