Background: Preclinical models that preserve the tumor microenvironment are critically needed in prostate cancer (PCa) research. Patient-derived xenografts (PDXs) and patient-derived Organotypic Slice Cultures (PD-OSCs) have emerged as promising in vivo and ex vivo platforms to address this gap and better mimic human tumor biology. Methods: Subcutaneous PDX models and PD-OSCs were established in parallel from fresh, primary hormone-naïve PCa patient tissues. PDX models were generated by engrafting tumor fragments into immunodeficient mice, while PD-OSCs were maintained as short-term ex vivo cultures for functional analysis. Results: A cohort of 64 PDXs and 45 PD-OSCs was generated. While first-generation PDX engraftment was successful, subsequent passaging and model expansion were extremely poor. In contrast, PD-OSCs were reliably established, maintained tissue viability, and proved to be a robust platform for functional testing, including gene expression analysis and drug sensitivity screening. Conclusions: Our findings establish both first-generation PDXs and PD-OSCs as valuable “avatar” models for translational research. However, PD-OSCs represent a more efficient and rapid platform for studying primary hormone-naïve PCa biology and evaluating treatment responses, holding significant promise as a predictive tool to guide personalized medicine.

Background/Objectives: Metastatic prostate cancer (PCa) remains a major clinical challenge with limited therapeutic options. The long non-coding RNA H19 has been implicated in regulating cell adhesion molecules and collective migration, key features of metastatic dissemination. This study investigates the role of the Bromodomain and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 in the H19-dependent transcriptional regulation of cell adhesion molecules. Currently, the major effects of BET inhibitors require androgen receptor (AR) expression. Methods: H19 was stably silenced in PC-3 (AR-null) and 22Rv1 (AR-positive) castration-resistant PCa cells. The cells were treated with the pan-BET inhibitors JQ1 and OTX015 or the BET degrader dBET6. In vivo, the effects of JQ1 were evaluated in xenograft mouse models. Chromatin immunoprecipitation (ChIP) and RNA-ChIP were used to assess BET protein recruitment and interaction with cell adhesion gene loci and H19. Organotypic slice cultures (OSCs) from fresh PCa surgical specimens were used as ex vivo models to validate transcriptional changes and BRD4 recruitment. Results: BET inhibition significantly reduced the expression of β4 integrin and E-cadherin and cell proliferation in both basal conditions, and following H19 knockdown in PC-3 and 22Rv1 cells. These effects were mirrored in JQ1-treated tumor xenografts, which showed marker downregulation and tumor regression. ChIP assays revealed that BRD4, more than BRD2/3, was enriched on β4 integrin and E-cadherin promoters, especially in regions marked by H3K27ac. H19 silencing markedly enhanced BRD4 promoter occupancy. RNA-ChIP confirmed a specific interaction between BRD4 and H19. These findings were validated in OSCs, reinforcing their clinical relevance. Conclusions: Our study demonstrates that BRD4 epigenetically regulates the H19-mediated transcriptional control of adhesion molecules involved in collective migration and metastatic dissemination. Importantly, these effects are independent of AR status, suggesting that targeting the H19/BRD4 axis may represent a promising therapeutic avenue for advanced PCa.