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

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

PROVIDER: PRJNA481738 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7536900_1.fastq.gz	Fastqsanger.gz
	SRR7536900_2.fastq.gz	Fastqsanger.gz
	SRR7536910_1.fastq.gz	Fastqsanger.gz
	SRR7536910_2.fastq.gz	Fastqsanger.gz
	SRR7536920_1.fastq.gz	Fastqsanger.gz

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N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer

Project description:N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer

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

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

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

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

| PRJNA481737 | ENA

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.

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N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer.

Project description:Despite recent therapeutic advances, prostate cancer remains a leading cause of cancer-related death. A subset of castration resistant prostate cancers become androgen receptor (AR) signaling-independent and develop neuroendocrine prostate cancer (NEPC) features through lineage plasticity. These NEPC tumors, associated with aggressive disease and poor prognosis, are driven, in part, by aberrant expression of N-Myc, through mechanisms that remain unclear. Integrative analysis of the N-Myc transcriptome, cistrome and interactome using in vivo, in vitro and ex vivo models (including patient-derived organoids) identified a lineage switch towards a neural identity associated with epigenetic reprogramming. N-Myc and known AR-co-factors (e.g., FOXA1 and HOXB13) overlapped, independently of AR, at genomic loci implicated in neural lineage specification. Moreover, histone marks specifically associated with lineage-defining genes were reprogrammed by N-Myc. We also demonstrated that the N-Myc-induced molecular program accurately classifies our cohort of patients with advanced prostate cancer. Finally, we revealed the potential for EZH2 inhibition to reverse the N-Myc-induced suppression of epithelial lineage genes. Altogether, our data provide insights on how N-Myc regulates lineage plasticity and epigenetic reprogramming associated with lineage-specification. The N-Myc signature we defined could also help predict the evolution of prostate cancer and thus better guide the choice of future therapeutic strategies.

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N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

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FOXA2/AP-1 drives prostate cancer lineage plasticity [ChIP-seq]

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