Ena-DATASET-UOMCAP-24-11-2020-23:19:59:840-777 - samples
Ontology highlight
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PROVIDER: EGAD00001006640 | EGA |
REPOSITORIES: EGA
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Project description:Following androgen ablation therapy (AAT), the vast majority of prostate cancer patients develop treatment resistance with a median time of 18-24 months to disease progression. To identify molecular targets that aid in prostate cancer cell survival and contribute to the androgen independent phenotype, we evaluated changes in LNCaP cell gene expression during 12 months of androgen deprivation. At time points reflecting critical growth and phenotypic changes, we performed Affymetrix expression array analysis to examine the effects of androgen deprivation during the acute response, during the period of apparent quiescence, and during the emergence of highly proliferative, androgen-independent prostate cancer cells (LNCaP-AI). We discovered alterations in gene expression for a host of molecules associated with promoting prostate cancer cell growth and survival, regulating cell cycle progression, apoptosis and adrenal androgen metabolism, in addition to AR co-regulators and markers of neuroendocrine disease. These findings illustrate the complexity and unpredictable nature of cancer cell biology and contribute greatly to our understanding of how prostate cancer cells likely survive AAT. The value of this longitudinal approach lies in the ability to examine gene expression changes throughout the cellular response to androgen deprivation; it provides a more dynamic illustration of those genes which contribute to disease progression in addition to specific genes which constitute a malignant androgen-independent phenotype. In conclusion, it is of great importance that we employ new approaches, such as the one proposed here, to continue exploring the cellular mechanisms of therapy resistance and identify promising targets to improve cancer therapeutics. Experiment Overall Design: To identify molecular targets that aid in prostate cancer cell survival and contribute to the androgen independent phenotype, we evaluated changes in LNCaP cell gene expression during 12 months of androgen deprivation. At time points reflecting critical growth and phenotypic changes, we performed Affymetrix expression array analysis to examine the effects of androgen deprivation during the acute response, during the period of apparent quiescence, and during the emergence of highly proliferative, androgen-independent prostate cancer cells (LNCaP-AI).
2008-04-07 | E-GEOD-8702 | biostudies-arrayexpress
Project description:Androgen deprivation is a standard of care front-line therapy for human prostate cancer, however, majority of patients will eventally develop resistance to androgen deprivation. In this study, using a human prostate cancer xenograft model -LuCaP35, we examiend the gene expression changes after castration.
2011-12-06 | GSE33316 | GEO
Project description:Androgen deprivation is a standard of care front-line therapy for human prostate cancer, however, majority of patients will eventally develop resistance to androgen deprivation. In this study, using a human prostate cancer xenograft model -LuCaP35, we examiend the gene expression changes after castration. We compare the gene expression of 5 LuCaP35 xenografts from non-treated mice (Control), and 5 androgen-deprived LuCaP35 xenografts from castrated mice (Castration).
2011-12-06 | E-GEOD-33316 | biostudies-arrayexpress
Project description:A subpopulation of prostate luminal epithelial cells has been previously reported to be sufficient to regenerate prostatic architecture following consecutive rounds of androgen deprivation/repletion. This functional characteristic suggest prostate luminal epithelial cells as the putative cell-of-origin for castration-resistant prostate cancer - which more notizable fenotype is the lack of response to androgen deprivation thereapy. We used microarrays to profile the androgen-induced transcripts in luminal prostate epithelial cells involved in a cycle of prostate regression/regeneration in Hoxb13-rtTA|TetO-H2BGFP transgenic mice.
2021-04-06 | GSE171490 | GEO
Project description:Androgen-deprivation therapy (ADT) is the standard of care for the treatment of non-resectable prostate cancer (PCa). Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we perform a comparative proteomic analysis of three in vivo, androgen receptor (AR)–driven, orthograft models of CRPC. Differential proteomic analysis reveals that distinct molecular mechanisms, including amino acid (AA) and fatty acid (FA) metabolism, are involved in the response to ADT between the different models. Despite this heterogeneity, we identify SLFN5 as an AR-regulated biomarker in CRPC. SLFN5 expression is high in CRPC tumours and correlates with poor patient outcome. In vivo, SLFN5 depletion strongly impairs tumour growth in castrated condition. Mechanistically, SLFN5 interacts with ATF4 and regulates the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreases intracellular levels of essential AA and impairs mTORC1 signalling in a LAT1-dependent manner.
2022-10-14 | PXD021405 | Pride
Project description:Androgen-deprivation therapy (ADT) is the standard of care for the treatment of non-resectable prostate cancer (PCa). Despite high treatment efficiency, most patients ultimately develop lethal castration-resistant prostate cancer (CRPC). In this study, we perform a comparative proteomic analysis of three in vivo, androgen receptor (AR)–driven, orthograft models of CRPC. Differential proteomic analysis reveals that distinct molecular mechanisms, including amino acid (AA) and fatty acid (FA) metabolism, are involved in the response to ADT between the different models. Despite this heterogeneity, we identify SLFN5 as an AR-regulated biomarker in CRPC. SLFN5 expression is high in CRPC tumours and correlates with poor patient outcome. In vivo, SLFN5 depletion strongly impairs tumour growth in castrated condition. Mechanistically, SLFN5 interacts with ATF4 and regulates the expression of LAT1, an essential AA transporter. Consequently, SLFN5 depletion in CRPC cells decreases intracellular levels of essential AA and impairs mTORC1 signalling in a LAT1-dependent manner.
2022-04-06 | PXD021428 | Pride
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:Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Prior work has focused on targeting AR directly; however, the identification and targeting of co-activators of AR signaling remains an underexplored area. Here we demonstrate that the MLL (mixed-lineage leukemia) complex, a well-known contributor in MLL-fusion-positive leukemia, acts as a co-activator of AR signaling. AR interacts with the MLL complex via its subunit, menin. Small molecule inhibition of the menin-MLL interaction blocks AR signaling and inhibits tumor growth in vivo. Furthermore, we find that menin is up-regulated in CRPC and high expression correlates with poor overall survival. Our study identifies the MLL complex as a co-activator of AR that can be targeted in advanced prostate cancer. ASH2L / Menin / MLL1 were knocked down using shRNA /siRNA in two prostate cancer cell lines, VCaP and LNCaP.
2015-03-02 | E-GEOD-60836 | biostudies-arrayexpress
Project description:Benign prostate tissue and prostate cancer tissue (untreated, androgen deprivation therapy responding, or castrate-resistant) was collected from patients at the time of transurethral resection of the prostate surgery. 24 samples, technical replicates.
2012-12-01 | E-GEOD-28680 | biostudies-arrayexpress
Project description:Benign prostate tissue and prostate cancer tissue (untreated, androgen deprivation therapy responding, or castrate-resistant) was collected from patients at the time of transurethral resection of the prostate surgery.
2012-12-01 | GSE28680 | GEO