Resistance to AR Signaling Inhibition Does Not Necessitate Prostate Neuroendocrine Differentiation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA673135 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12933407_1.fastq.gz | Fastqsanger.gz | |||
| SRR12933407_2.fastq.gz | Fastqsanger.gz | |||
| SRR12933408_1.fastq.gz | Fastqsanger.gz | |||
| SRR12933408_2.fastq.gz | Fastqsanger.gz | |||
| SRR12933409_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 124 |
Similar Datasets
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: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:Androgen receptor (AR) signaling is a distinctive feature of prostate cancer (PC) and represents the major therapeutic target for the treatment of metastatic disease. Though highly effective, AR antagonism has the potential to generate tumors that bypass a functional requirement for AR activity. We show here that a phenotypic shift has occurred in metastatic PCs with the emer-gence of a double-negative AR-null neuroendocrine-null phenotype that is notable for MAPK and FGF pathway activity. To identify mechanisms capable of sustaining PC survival, we gener-ated a model system designated AR program-independent prostate cancer (APIPC) which re-sists AR-targeted therapeutics, lacks neuroendocrine features, expresses high levels of FGF8 and the ID1 oncogene, and activates MAPK signaling. Pharmacological blockade of MAPK or FGF signaling inhibited APIPC tumor growth, supporting FGF/MAPK as a therapeutic avenue for treating AR-null PC.
2017-10-09 | GSE99381 | GEO
Project description:Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of neuroendocrine prostate cancer (NEPC), a phenomenon associated with enhanced cell plasticity. Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer samples, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signalling. Over-expression of miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity. One such target gene was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features. Overall, our study reveals a post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in NEPC.
2019-09-09 | GSE137071 | GEO
Project description:Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of neuroendocrine prostate cancer (NEPC), a phenomenon associated with enhanced cell plasticity. Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer samples, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signalling. Over-expression of miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity. One such target gene was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features. Overall, our study reveals a post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in NEPC.
2019-09-09 | GSE137070 | GEO
Project description:Prostate cancer is the most common cancer in men and AR downstream signalings promote prostate cancer cell proliferation. Oct1 is an AR interacting partner and regulates the transcriptional activity of AR. In order to investigate the Oct1 function in prostate cancer cells, we performed gene expression in AR-positive prostate cancer cell lines after siOct1 or pyrrole-imidazole (PI) polyamide targeting Oct1-binding treatment. We also treated cells with vehicle or androgen to analyze the effects of Oct1 on AR function. Observation of androgen dependent gene expression changes after treatment with siOct1 or polyamide targeting Oct1 with microarray.
2016-04-01 | E-GEOD-77650 | biostudies-arrayexpress
Project description:Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of neuroendocrine prostate cancer (NEPC), a phenomenon associated with enhanced cell plasticity. Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer samples, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signalling. Over-expression of miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity. One such target gene was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features. Overall, our study reveals a post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in NEPC.
2020-11-30 | GSE162319 | GEO
Project description:Background: Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer, is characterized by loss of AR signaling and resulting resistance to AR-targeted therapy during neuroendocrine transdifferentiation, for which the molecular mechanisms remain unclear. Here, we report that SRY-Box transcription factor 4 (SOX4) is upregulated in NEPC, which induces neuroendocrine markers, neuroendocrine cell morphology, and NEPC cell aggressive behavior. Methods: To understand the function of SOX4 in the development and progression of NEPC, we detected malignancy characterization after over-expression or knock-down of SOX4 in prostate cancer cells. Xenograft tumors representing NEPC subtypes were analyzed by pathologists. Protein expression profiles were validated in patient tumor tissue. Diagnoses were complemented by transcriptome sequencing and ATAC sequencing of specific cell lines and public clinical datasets. Results: SOX4 expression was significantly elevated in NEPC. Activating SOX4 in non-NEPC cells induced NE transdifferentiation, while silencing it in NEPC cells impeded NEPC progression. SOX4 promote neuroendocrine characteristics by inducing PCK2-mediated metabolism changing. Conclusions: Elevated SOX4 drives NE transdifferentiation in PCa via PCK2-mediated . Altogether, these findings highlight SOX4 as a novel molecule to drive NEPC progression and suggest that it might be a potential therapeutic target for NEPC.
2024-03-31 | GSE261370 | GEO