RNA-seq analysis of metastatic prostate cancer solid tumor biopsies
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001006369 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Resistance to androgen deprivation therapies leads to metastatic castration-resistant prostate cancer (mCRPC) of adenocarcinoma (AdCa) origin that can transform to emergent aggressive variant prostate cancer (AVPC) which has neuroendocrine (NE)-like features. To this end, we used LuCaP patient-derived xenograft (PDX) tumors, clinically relevant models that reflects and retains key features of the tumor from advanced prostate cancer patients. Here we performed proteome and phosphoproteome characterization of 48 LuCaP PDX tumors and identified over 94,000 peptides and 9,700 phosphopeptides corresponding to 7,738 proteins. When we compared 15 NE versus 33 AdCa PDX samples, we identified 309 unique proteins and 476 unique phosphopeptides that were significantly altered and corresponded to proteins that are known to distinguish these two phenotypes. Assessment of protein and RNA concordance from these tumors revealed increased dissonance in transcriptionally regulated proteins in NE and metabolite interconversion enzymes in AdCa.
Keywords: Proteomics, phosphoproteomics, Neuroendocrine, Adenocarcinoma, biomarkers, surfaceome, secretome, blood proteins, prostate cancer, patient-derived xenograft
2023-06-09 | MSV000092139 | MassIVE
Project description:Resistance to androgen deprivation therapies leads to metastatic castration-resistant prostate cancer (mCRPC) of adenocarcinoma (AdCa) origin that can transform to emergent aggressive variant prostate cancer (AVPC) which has neuroendocrine (NE)-like features. To this end, we used LuCaP patient-derived xenograft (PDX) tumors, clinically relevant models that reflects and retains key features of the tumor from advanced prostate cancer patients. Here we performed proteome and phosphoproteome characterization of 48 LuCaP PDX tumors and identified over 94,000 peptides and 9,700 phosphopeptides corresponding to 7,738 proteins. When we compared 15 NE versus 33 AdCa PDX samples, we identified 309 unique proteins and 476 unique phosphopeptides that were significantly altered and corresponded to proteins that are known to distinguish these two phenotypes. Assessment of protein and RNA concordance from these tumors revealed increased dissonance in transcriptionally regulated proteins in NE and metabolite interconversion enzymes in AdCa.
2023-06-09 | MSV000092137 | MassIVE
Project description:Neuroendocrine (NE) differentiation in metastatic castration-resistant prostate cancer (mCRPC) usually develops through cellular plasticity. We recently characterized two mCRPC phenotypes with NE features; Androgen receptor (AR)-positive, NE-positive amphicrine prostate cancer (AMPC) and AR-negative small cell or neuroendocrine prostate cancer (SCNPC). Here, we interrogate the RE-1 silencing transcription factor (REST) pathway in mCRPC and demonstrate that SRRM3 has analogous functions to SRRM4 and mediates NE differentiation through alternative splicing of REST. We scrutinize transcriptome datasets across species and tumor types and discover that SRRM3 and SRRM4 expression define molecular phenotypes in AMPC and SCNPC. Notably, we characterize two AMPC phenotypes driven by either REST attenuation or ASCL1 activity and three SCNPC phenotypes with progressive activation of neuronal transcription factor programs. Together, our data provides a biological framework for classifying NE phenotypes in mCRPC that could be useful for future therapeutic development and precision medicine applications.
2021-07-14 | GSE158598 | GEO
Project description:Neuroendocrine (NE) differentiation in metastatic castration-resistant prostate cancer (mCRPC) usually develops through cellular plasticity. We recently characterized two mCRPC phenotypes with NE features; Androgen receptor (AR)-positive, NE-positive amphicrine prostate cancer (AMPC) and AR-negative small cell or neuroendocrine prostate cancer (SCNPC). Here, we interrogate the RE-1 silencing transcription factor (REST) pathway in mCRPC and demonstrate that SRRM3 has analogous functions to SRRM4 and mediates NE differentiation through alternative splicing of REST. We scrutinize transcriptome datasets across species and tumor types and discover that SRRM3 and SRRM4 expression define molecular phenotypes in AMPC and SCNPC. Notably, we characterize two AMPC phenotypes driven by either REST attenuation or ASCL1 activity and three SCNPC phenotypes with progressive activation of neuronal transcription factor programs. Together, our data provides a biological framework for classifying NE phenotypes in mCRPC that could be useful for future therapeutic development and precision medicine applications.
2021-07-14 | GSE158593 | GEO
Project description:Achieved biospecimens annotated with patient clinical characteristics are unique resources for translational research. However, RNA extracted from the achieved tissues is often degraded. RNA degradation can have a significant impact on the measure of transcript abundance that can lead to an increase rate of erroneous differentially expressed genes. Here, we are presenting the transcript integrity number (TIN) algorithm to measure the RNA degradation at transcript level. When applied to RNA-seq datasets generated from human brain Glioblastome cell line, human peripheral blood mononuclear cells, and metastatic castration resistant prostate cancer (mCRPC) clinical tissues, TIN provided a more reliable and more sensitive measure of RNA degradation than RIN, as demonstrated by much higher concordance with the RNA fragment size estimated from read pairs. More importantly, when comparing 10 mCRPC samples with lower RNA quality to another 10 samples with higher RNA quality, we demonstrated that calibrating gene quantification with TIN scores could mitigate RNA degradation effects and greatly improve gene expression analysis. The detected differentially expressed genes before TIN correction were predominantly ribosomal genes. However, when we adjusted gene quantifications with the corresponding TIN scores, we found differentially expressed genes were highly enriched in prostate cancer specific pathways. When further evaluating the performance of TIN correction using synthetic spike-in transcripts with predetermined abundance in RNA-seq data generated from Sequencing Control Consortium (SEQC), we found TIN adjustment had a better control of false positives and false negatives (sensitivity = 0.89, specificity = 0.91), as compared to gene expression analysis results without TIN correction (sensitivity =0.98, specificity = 0.50). RNA sequencing of 20 bone-metastatic castration resistant prostate cancer (mCRPC) using Illumina HiSeq 2500. Out of 20 mCRPC samples, 10 samples have relative low RNA integrity and another 10 samples have relative higher RNA integrity as measured by Agilent RIN score.
2016-02-19 | E-GEOD-70285 | biostudies-arrayexpress
Project description:The widespread and long-term use of potent therapies designed to repress androgen receptor (AR) signaling is changing the molecular and phenotypic landscapes of prostate cancer. We conducted molecular profiling of metastatic castration-resistant prostate cancer (mCRPC) patient specimens and patient-derived xenograft models and identified five distinct mCRPC phenotypes. Herein, we characterize an AR-low phenotype that has low AR expression with concomitant decreases in a subset of AR regulated genes, and an amphicrine phenotype that has both AR and neuroendocrine activity in the same cell. Furthermore, our data highlight an emerging squamous cell mCRPC phenotype.
2019-07-17 | GSE126078 | GEO
Project description:There are many treatment options available for men with metastatic castration-resistant prostate cancer (mCRPC). Yet, biomarkers predictive of differential response to treatment are currently available. A recent translational study suggested that SLCO2B1 genotype could predict response to abiraterone acetate (AA) for men with advanced prostate cancer. Here, we investigate whether germline variants in SLCO2B1 are predictive of response to first-line AA in men with new mCRPC. Clinical data and samples were analyzed from a prospective prostate cancer registry at the University of Utah. Genotyping was performed using the Illumina OmniExpress genotyping platform. Primary endpoint was progression-free survival (PFS) on first-line AA in men with mCRPC. We performed a pre-specified multivariate Cox regression analysis to assess the independent predictive value of rs12422149 and rs1789693 on PFS on AA. Of 401 men with advanced prostate cancer genotyped, 323 were homozygous wild type for rs12422149 (80.5%), 74 were heterozygous (18.5%), and 4 were homozygous variant (1.0%). In a multivariate analysis of 79 men treated with first-line AA for mCRPC, men heterozygous for rs12422149 had significantly improved median PFS compared to the homozygous wild-type group (8.9 months vs. 6.3 months, HR 0.46, 95% CI 0.23-0.94, p=0.03). No significant difference in median PFS was seen by rs1789693 genotype. In this first clinical validation of translational data reported by Mostaghel and colleagues, germline variant alleles in rs12422149 of SLCO2B1 are common and predict improved response to first-line AA In men with mCRPC.
2018-12-13 | GSE123695 | GEO
Project description:Higher expression levels of DLX1 has been associated with primary and metastatic prostate tumor. DLX1 along with HOXC6 is well-established diagnostic biomarker for the early detection of prostate cancer (PCa). However, the mechanism involved in DLX1 up-regulation and functional significance in metastatic castration-resistant prostate cancer (mCRPC) progression remains unexplored. Here, we identified that DLX1 serves as an oncogene thereby regulating several oncogenic properties associated with PCa progression.
2021-07-30 | GSE138738 | GEO
Project description:Enzalutamide (ENZA) is a frequently used therapy in metastatic castration-resistant prostate cancer (mCRPC). Baseline or acquired resistance to ENZA have been observed, but the molecular mechanisms of resistance are poorly understood. We aimed to identify proteins involved in ENZA resistance and to find therapy-predictive serum markers. We performed comparative proteome analyses on ENZA-sensitive parental (LAPC4, DUCAP) and -resistant prostate cancer cell lines (LAPC4-ENZA, DUCAP-ENZA) using liquid chromatography tandem mass spectrometry (LC-MS/MS). The most promising 4 marker candidates were selected using bioinformatic approaches. Serum concentrations of selected markers (ALCAM, AGR2, NDRG1, IDH1) were measured in 72 ENZA-treated mCRPC patients’ samples using ELISA. In addition, ALCAM serum levels were measured in 101 Abiraterone (ABI) and 100 Docetaxel (DOC)-treated mCRPC patients. Results were correlated with clinical and follow-up data. The functional role of ALCAM in ENZA resistance was assessed in vitro using siRNA. Our proteome analyses revealed 731 significantly differentially abundant proteins between ENZA-sensitive and -resistant cells and our filtering methods identified 4 biomarker candidates. Serum analyses of these proteins revealed only ALCAM to be associated with poor patient survival. Furthermore, higher baseline ALCAM levels were associated with poor survival in ABI- but not in DOC-treated patients. In LAPC4-ENZA resistant cells, ALCAM silencing by siRNA knockdown resulted in significantly enhanced ENZA sensitivity. Our analyses revealed that ALCAM serum levels may help to identify ENZA- and ABI-resistant patients and may thereby help to optimize future clinical decision-making. Our functional analyses suggest the possible involvement of ALCAM in ENZA resistance.
2022-06-24 | PXD031847 | Pride
Project description:Background: Abiraterone (Abi) is an androgen receptor signaling inhibitor that significantly improves patients' life expectancy in metastatic prostate cancer (PCa). Despite its beneficial effects, many patients have baseline or acquired resistance against Abi. Objective: To identify predictive serum biomarkers for Abi treatment. Design, setting, and participants: We performed a comparative proteome analysis on three Abi sensitive (LNCaPabl, LAPC4, DuCaP) and resistant (LNCaPabl-Abi, LAPC4-Abi, DuCaP-Abi) PCa cell lines using liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. Two bioinformatic selection methods were applied to select the most promising candidate serum markers. Serum levels of selected proteins were assessed in samples of 100 Abi-treated patients with metastatic castration-resistant disease using ELISA. Moreover, FSCN1 serum concentrations were measured in samples of 69 Docetaxel (Doc) treated mCRPC patients. Outcome measurements and statistical analysis: Serum levels were correlated with patients‘ clinicopathological parameters and survival. Results and limitations: Our proteome analysis identified 68 significantly, at least two-fold upregulated proteins in Abi resistant cells. Using two filtering methods four proteins (AMACR, KLK2, FSCN1 and CTAG1A) were selected for ELISA analyses. We found high baseline FSCN1 serum levels to be significantly associated with poor survival in Abi-treated mCRPC patients. Moreover, the multivariable analysis revealed that higher ECOG status (>1) and high baseline FSCN1 serum levels (>10.22 ng/ml by ROC cut-off) were independently associated with worse survival in Abi-treated patients (p<0.001 and p=0.021, respectively). In contrast, no association was found between serum FSCN1 concentrations and overall survival in Doc-treated patients. Conclusions: Our analysis identified baseline FSCN1 serum levels to be independently associated with poor survival of Abi-treated, but not Doc-treated mCRPC patients, suggesting a therapy specific prognostic value for FSCN1. Patient summary: In this study, we identified serum FSCN1 as a marker that may help to predict PCa patients who derive less benefit from Abi but not Doc treatment.
2023-08-28 | PXD038697 | Pride