Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE126078 | GEO | 2019/07/17
REPOSITORIES: GEO
Similar Datasets
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:<p>Adapted from manuscript in review:</p> <p>Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC) but there have been few whole genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. These include highly recurrent tandem duplications involving an upstream enhancer of AR. A subset of cases also displayed a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC nominate new alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the noncoding mCRPC genome remain to be discovered. </p>
| phs001577 | dbGaP
Project description:Resistance to 2nd generation androgen receptor (AR) signaling inhibitors (ARSi) occurs in a subset of metastatic castration-resistant prostate cancer (mCRPC) patients with the emergence of a neuroendocrine (NE) phenotype. This NE phenotype is typically accompanied by loss of AR expression coupled with mutations/deletions in PTEN, TP53, and/or RB1, in addition to overexpression of DNMTs, EZH2, and/or SOX2. A combination of cell and molecular biology analyses of 29 prostate cancer patient-derived xenografts (PDXs) recapitulating the full spectrum of proposed genetic alterations driving NE differentiation, in addition to CRISPR-Cas9 AR-knockout cells were utilized. These analyses document that: 1) ARSi-resistance in mCRPC cells that lack AR expression in the context of a TP53 mutation and PTEN deletion does not necessitate acquiring a NE phenotype, but alternatively can occur via emergence of an AR-/NE- double negative (DN) cancer; 2) NE cancers lack AR expression due to transcriptional silencing via promoter hypermethylation; and 3) in contrast, the lack of AR expression in DN cancers is not due to promoter hypermethylation-dependent silencing. Regardless of their cell of origin, the prevalence of both AR-/NE- DN and AR-/NE+ ARSi-resistant cancers is increasing clinically, highlighting the urgent need to develop therapies that target vulnerabilities beyond AR pathway inhibition.
2021-04-01 | GSE160393 | GEO
Project description:Increased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation anti-androgen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost androgen receptor (AR) signaling. AVPC tumors may also express neuroendocrine markers, termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing AR-negative to AR-positive prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-negative cell lines. Clinical NEPC and NEPC patient derived xenografts displayed upregulated RET transcript and RET pathway activity. Pharmacologically inhibiting RET kinase in NEPC models dramatically reduced tumor growth and cell viability in mouse and human NEPC models. Our results suggest that targeting RET in NEPC tumors with high RET expression may be a novel treatment option.
2020-05-29 | PXD012971 | Pride
Project description:Increased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation anti-androgen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost androgen receptor (AR) signaling. AVPC tumors may also express neuroendocrine markers, termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing AR-negative to AR-positive prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-negative cell lines. Clinical NEPC and NEPC patient derived xenografts displayed upregulated RET transcript and RET pathway activity. Pharmacologically inhibiting RET kinase in NEPC models dramatically reduced tumor growth and cell viability in mouse and human NEPC models. Our results suggest that targeting RET in NEPC tumors with high RET expression may be a novel treatment option.
2020-05-29 | PXD012970 | Pride
Project description:The neuroendocrine (NE) phenotype is associated with the development of metastatic castration-resistant prostate cancer (CRPC). Our objective was to characterize the molecular features of the NE phenotype in CRPC. Expression of chromogranin A (CHGA), synaptophysin (SYP), androgen receptor (AR), and prostate-specific antigen (PSA) was analyzed by immunohistochemistry (IHC) in 155 CRPC metastases from 50 patients and in 24 LuCaP prostate cancer patient-derived xenografts (PDX). Co-expression of CHGA and SYP in >30% of cells was observed in 22 of 155 metastases (9 patients); 11 of the 22 metastases were AR+/PSA+ (6 patients), 11/22 were AR-/PSA- (4 patients), and 4/24 LuCaP PDXs were AR-/PSA-. Seventy-one of 155 metastases and the 24 LuCaP xenograft lines were analyzed by whole genome microarrays. By IHC, of the 71 metastases analyzed by whole genome microarrays, 5 metastases were CHGA+/SYP+/AR- and 5 were CHGA+/SYP+/AR+. Only CHGA+/SYP+ metastases had a NE transcript signature. The neuronal transcriptional regulator SRRM4 transcript was associated with the NE signature in CHGA+/SYP+ metastases and all CHGA+/SYP+ LuCaP xenografts. Additionally, expression of SRRM4 in the LuCaP NE xenografts correlated with a splice variant of REST that lacks the transcriptional repressor domain. In conclusion, (a) metastatic NE status can be heterogeneous in the same patient, (b) the CRPC NE molecular phenotype can be defined by CHGA+/SYP+ dual positivity, (c) the NE phenotype is not necessarily associated with the loss of AR activity, and (d) the splicing of REST by SRRM4 could promote the NE phenotype in CRPC. Custom Agilent 44K whole human genome expression oligonucleotide microarrays were used to profile 24 LuCaP PCa xenograft lines and 71 CRPC metastases from 47 patients. RNA was amplified prior to hybridization against a common reference pool of prostate tumor cell lines.
2015-06-24 | E-GEOD-66187 | biostudies-arrayexpress
Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.
2023-10-11 | MTBLS8034 | MetaboLights
Project description:The neuroendocrine (NE) phenotype is associated with the development of metastatic castration-resistant prostate cancer (CRPC). Our objective was to characterize the molecular features of the NE phenotype in CRPC. Expression of chromogranin A (CHGA), synaptophysin (SYP), androgen receptor (AR), and prostate-specific antigen (PSA) was analyzed by immunohistochemistry (IHC) in 155 CRPC metastases from 50 patients and in 24 LuCaP prostate cancer patient-derived xenografts (PDX). Co-expression of CHGA and SYP in >30% of cells was observed in 22 of 155 metastases (9 patients); 11 of the 22 metastases were AR+/PSA+ (6 patients), 11/22 were AR-/PSA- (4 patients), and 4/24 LuCaP PDXs were AR-/PSA-. Seventy-one of 155 metastases and the 24 LuCaP xenograft lines were analyzed by whole genome microarrays. By IHC, of the 71 metastases analyzed by whole genome microarrays, 5 metastases were CHGA+/SYP+/AR- and 5 were CHGA+/SYP+/AR+. Only CHGA+/SYP+ metastases had a NE transcript signature. The neuronal transcriptional regulator SRRM4 transcript was associated with the NE signature in CHGA+/SYP+ metastases and all CHGA+/SYP+ LuCaP xenografts. Additionally, expression of SRRM4 in the LuCaP NE xenografts correlated with a splice variant of REST that lacks the transcriptional repressor domain. In conclusion, (a) metastatic NE status can be heterogeneous in the same patient, (b) the CRPC NE molecular phenotype can be defined by CHGA+/SYP+ dual positivity, (c) the NE phenotype is not necessarily associated with the loss of AR activity, and (d) the splicing of REST by SRRM4 could promote the NE phenotype in CRPC.
2015-06-24 | GSE66187 | GEO
Project description:The objective of this study is to identify gene signature associated with castration-refractory prostate cancer (CRPC) development. We carried out RNA-seq based transcriptome profiling using 45 prostate samples with various disease progression steps such as benign prostate hyperplasia (BPH), primary cancer of prostate (CaP), advanced CaP and CRPC. Via various statistical analyses, we identified significant gene set associated with each progression step and observed that AR was the only gene feature associated with all progression steps, indicating that AR is the crucial mediator of and has a diverse activity across the CaP progressions. Among the samples in this data set, there are 4 pairs of advanced CaP and CRPC samples, in which each pair was obtained from the same patient. Using these paired samples, we also determined differentially expressed genes between advanced CaP and CRPC, and performed comparative analysis of significant gene lists in matched sample pairs and in unpaired remained samples. By assessing expression difference between advanced CaP and CRPC groups, 309 and 182 genes were statistically significant in paired and unpaired samples, respectively (P < 0.001). When these two gene lists were compared, a total of 15 genes were common and applied to a number of downstream experimental assays.
2018-04-22 | GSE80609 | GEO