Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer [RNA-seq]

ABSTRACT: Despite recent advances in highly effective androgen receptor (AR)-directed therapies for the treatment of prostate cancer, a significant subset of patients with resistant disease develop AR-null, androgen signaling-indifferent neuroendocrine prostate cancer (NEPC). A majority of these NEPC cases that arise following anti-androgen therapy are driven by the aberrant expression of the transcription factor N-Myc. To define the cell lineage states associated with the development of prostate cancer resistance phenotypes, we analyzed whole transcriptome data from a cohort of primary and metastatic tumors compared to benign tissues. NEPC tumors are significantly enriched for stem cell genes associated with embryonic and neural crest lineages, as well as for neural lineage-defining genes. Analysis of the N-Myc transcriptome, cistrome and chromatin-bound interactome using in vivo (GEMM and human xenografts), in vitro (human prostate cancer cell lines) and ex vivo models (NEPC-patient-derived organoids) revealed that the N-Myc cistrome is androgen-dependent and drives a transcriptional program that leads to epithelial plasticity and the acquisition of clinically-relevant neural lineage markers. Moreover, we show that histone marks specifically associated with lineage-defining genes are epigenetically reprogrammed by N-Myc. Finally, we demonstrate how N-Myc-induced gene expression and epigenetic changes can accurately classify patients with advanced prostate cancer which may provide a molecular signature to inform future therapeutic strategies.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE117305 | GEO | 2019/08/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer [ChIP-seq]

Project description:Despite recent advances in highly effective androgen receptor (AR)-directed therapies for the treatment of prostate cancer, a significant subset of patients with resistant disease develop AR-null, androgen signaling-indifferent neuroendocrine prostate cancer (NEPC). A majority of these NEPC cases that arise following anti-androgen therapy are driven by the aberrant expression of the transcription factor N-Myc. To define the cell lineage states associated with the development of prostate cancer resistance phenotypes, we analyzed whole transcriptome data from a cohort of primary and metastatic tumors compared to benign tissues. NEPC tumors are significantly enriched for stem cell genes associated with embryonic and neural crest lineages, as well as for neural lineage-defining genes. Analysis of the N-Myc transcriptome, cistrome and chromatin-bound interactome using in vivo (GEMM and human xenografts), in vitro (human prostate cancer cell lines) and ex vivo models (NEPC-patient-derived organoids) revealed that the N-Myc cistrome is androgen-dependent and drives a transcriptional program that leads to epithelial plasticity and the acquisition of clinically-relevant neural lineage markers. Moreover, we show that histone marks specifically associated with lineage-defining genes are epigenetically reprogrammed by N-Myc. Finally, we demonstrate how N-Myc-induced gene expression and epigenetic changes can accurately classify patients with advanced prostate cancer which may provide a molecular signature to inform future therapeutic strategies.

2019-08-26 | GSE117304 | GEO

Temporal evolution of cellular heterogeneity during the progression to advanced, AR-negative prostate cancer [scRNA-seq]

Project description:Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance ultimately ensues. A significant subset of patients with resistant disease develop AR-null, androgen-indifferent tumors that lose their luminal identify and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). Utilizing a genetically engineered mouse model, we have characterized the synergy between N-Myc overexpression and RB1 loss-of-function which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking changes to the transcriptome and chromatin accessibility during the transition to NEPC. Global DNA methylation and the N-Myc cistrome are redirected following RB1 loss. Altogether, our data provide new insight into the progression to NEPC.

2021-04-07 | GSE158468 | GEO

Temporal evolution of cellular heterogeneity during the progression to advanced, AR-negative prostate cancer [RNA-seq]

2021-04-07 | GSE158467 | GEO

Temporal evolution of cellular heterogeneity during the progression to advanced, AR-negative prostate cancer [RRBS]

2021-04-07 | GSE151581 | GEO

Temporal evolution of cellular heterogeneity during the progression to advanced, AR-negative prostate cancer [scATAC-seq]

2021-04-07 | GSE151425 | GEO

Temporal evolution of cellular heterogeneity during the progression to advanced, AR-negative prostate cancer [ChIP-seq]

2021-04-07 | GSE151424 | GEO

RET Kinase Inhibition in Neuroendocrine Prostate Cancer, part 2

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

RET Kinase Inhibition in Neuroendocrine Prostate Cancer, part 1

2020-05-29 | PXD012970 | Pride

ONECUT2 acts a lineage plasticity driver

Project description:Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease.

2024-08-10 | PXD050634 | Pride

MUC1-C Drives Lineage Plasticity in Progression to Neuroendocrine Prostate Cancer

Project description:Neuroendocrine prostate cancer (NEPC) is a highly aggressive malignancy of increasing prevalence with an unmet need for targeted therapeutic approaches. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC; however, there is no known role for MUC1-C in driving lineage plasticity to these advanced PC phenotypes. The present studies demonstrate that upregulation of MUC1-C in androgen-independent (AI) PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor by a previously unrecognized MYC-mediated mechanism. MUC1-C activates the BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP), which are linked to NEPC progression. We also show that MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Of potential clinical relevance, targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, supporting the treatment of CRPC and NEPC with agents directed against this oncoprotein. These findings and the demonstration that MUC1-C is upregulated and associated with suppression of AR signaling, and increases in BRN2 expression and the NEPC score in PC tissues highlight the unanticipated importance of MUC1-C as a master effector of lineage plasticity in progression to advanced PC with NE features.

2019-12-02 | GSE139335 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data