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Project description:Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen-deprivation remain poorly described despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild type mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin?/Sca-1+/CD49fmed). Here we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumorigenesis. In intact mice, we show that LSCmed prevalence remains low (5-10% of epithelial cells) when prostatic androgen receptor signaling unaltered (malignant Hi-Myc mice) but significantly increases in models exhibiting reduced prostatic androgen receptor signaling, rising up to 30% in premalignant tumors (Pb-PRL mice) and to >80% in castration-resistant prostate tumors driven by Pten loss (Ptenpc-/- mice). LSCmed tolerance to androgen deprivation was demonstrated by their persistence (Ptenpc-/-) or further enrichment (Pb-PRL) 2-3 weeks after castration as evidenced by FACS analysis. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene-expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signaling is markedly decreased, which explains why LSCmed tolerate androgen-deprivation. This also enlightens why Ptenpc-/- tumors are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Ptenpc-/- prostates, BrdU staining revealed massive proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. In all, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer.
2017-08-15 | E-MTAB-4991 | biostudies-arrayexpress
Project description:TMT-MS of whole cell lysate collected from 22Rv1 castration-resistant prostate cancer cells treated with 5 µM JG-98 for 4 hours.
2023-04-25 | PXD038684 | JPOST Repository
Project description:Clinical resection specimens of prostate tissue (radical prostatectomy and TUR-P) over the course of hormone deprivation therapy were flow sorted according to their DNA content (Ploidy) and subjected to aCGH analysis to identify possiple chromosomal abberations which could confer castration resistance.
2018-03-01 | GSE108203 | GEO
Project description:More effective therapeutic approaches for castration-resistant prostate cancer (CRPC) are urgently needed, thus reinforcing the need to understand how prostate tumors progress to castration resistance. We have established a novel mouse xenograft model of prostate cancer, KUCaP-2, which expresses the wild-type androgen receptor (AR) and which produces the prostate-specific antigen (PSA). In this model, tumors regress soon after castration, but then reproducibly restore their ability to proliferate after 1 to 2 months without AR mutation, mimicking the clinical behavior of CRPC. In the present study, we used this model to identify novel therapeutic targets for CRPC. Evaluating tumor tissues at various stages by gene expression profiling, we discovered that the prostaglandin E receptor EP4 subtype (EP4) was significantly upregulated during progression to castration resistance. Immunohistochemical results of human prostate cancer tissues confirmed that EP4 expression was higher in CRPC compared with hormone-naïve prostate cancer. Ectopic overexpression of EP4 in LNCaP cells (LNCaP-EP4 cells) drove proliferation and PSA production in the absence of androgen supplementation in vitro and in vivo. Androgen-independent proliferation of LNCaP-EP4 cells was suppressed when AR expression was attenuated by RNA interference. Treatment of LNCaP-EP4 cells with a specific EP4 antagonist, ONO-AE3-208, decreased intracellular cyclic AMP levels, suppressed PSA production in vitro, and inhibited castration-resistant growth of LNCaP-EP4 or KUCaP-2 tumors in vivo. Our findings reveal that EP4 overexpression, via AR activation, supports an important mechanism for castration-resistant progression of prostate cancer. Furthermore, they prompt further evaluation of EP4 antagonists as a novel therapeutic modality to treat CRPC. 4 samples in each group: androgen-dependent growth (AD), castration-induced regression nadir (ND), and castration-resistant regrowth (CR) stages
2010-06-08 | E-GEOD-21887 | biostudies-arrayexpress
Project description:Clinical resistance such as androgen receptor (AR) mutation, AR overexpression, and AR splice variants (ARVs) restrict the second-generation antiandrogens benefit in patients with castration-resistant prostate cancer (CRPC). Several strategies have been implemented to develop novel antiandrogens to circumvent the occurring resistance. In this study, based on rational drug design, we discovered and identified a bifunctional small molecule Z15 as a potent AR antagonist and AR selective degrader. Z15 could directly bind to the AR ligand-binding domain (LBD) and inhibited DHT-induced AR nuclear translocation. Furthermore, Z15 promoted AR degradation through the proteasome pathway. As a result, our in vitro and in vivo studies showed Z15 efficiently suppressed AR and AR mutant transcription activity, downregulated mRNA and protein levels of AR target genes, as well as overcame AR LBD mutations, AR amplification, and ARVs-induced resistance in CRPC. In conclusion, our data illustrate the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment.
2023-02-02 | PXD035721 | Pride
Project description:The transcription factor GATA2 regulates chemotherapy resistance in prostate cancer. We report a novel GATA2 transcriptional program that has implications for chemotherapy resistance disease and aggressiveness in castration resistant prostate cancer.
2014-11-04 | GSE58966 | GEO
Project description:To identify changes at multiple omic levels between hormone naive and castration resistant prostate cancer. Using orthograft murine tumour models of human cell lines injected into the prostate of CD-1 Nude mice grown under castration resistant (castrate) or hormone naive (non-castrate) conditions.
2021-05-03 | E-MTAB-9831 | biostudies-arrayexpress
Project description:The transcription factor GATA2 regulates chemotherapy resistance in prostate cancer. We report a novel GATA2 transcriptional program that has implications for chemotherapy resistance disease and aggressiveness in castration resistant prostate cancer. Examination of the transcriptional network changes induced in human Ch-CRPC cell lines by two shRNA mediated knock down of GATA2 versus random shRNA control
2014-11-04 | E-GEOD-58966 | biostudies-arrayexpress
Project description:Targeted disruption of the embryonic stem cell (ESC) self-renewal and pluripotency factor NANOG diminishes cancer cell clonogenic growth in vitro and tumor development in vivo. NANOG has also been shown to augment CSC properties and propel the emergence of castration-resistance prostate cancer (CRPC) phenotypes. Here, we investigate the molecular mechanisms underlying NANOG-mediated oncogenesis and prostate cancer progression to androgen independence. ChIP-Seq analysis of LNCaP prostate cancer cells overexpressing doxycycline-inducible NANOG (either NANOG1 or NANOGP8 vs pLVX control) reveal that NANOG coordinately occupies regions of chromatin regulated by AR signaling steroid-receptor complex proteins AR, FOXA1 and NKX3.1. Taken together with the NANOG-induced changes in the prostate cancer transcriptome (RNA-Seq), NANOG appears to reprogram prostate cancer cells to castration resistance by converging on steroid-hormone receptor signaling.
2016-11-08 | GSE74798 | GEO
Project description:aCGH experiment on cell-free DNA collected from the plasma of patients with castration-resistant prostate cancer. No replicates. castration-resistant prostate cancer vs male reference DNA
2015-03-09 | E-GEOD-61134 | biostudies-arrayexpress