PlexinD1 drives the lineage plasticity in advanced prostate cancer
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ABSTRACT:
PROVIDER: PRJNA1067089 | ENA |
REPOSITORIES: ENA
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Project description:N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer
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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 | GSE117305 | GEO
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
Project description:N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer [ChIP-seq]
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Project description:N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer [RNA-seq]
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Project description:Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance seen in 10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify SWI/SNF subunits that are deregulated in NEPC, demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease and that SMARCA4 depletion impairs prostate cancer cell growth. We also show that SWI/SNF complexes interact with different lineage-specific factors in prostate adenocarcinoma and in NEPC cells, and that induction of lineage plasticity through depletion of REST is accompanied by changes in SWI/SNF genome occupancy. These data suggest a specific role for mSWI/SNF complexes in therapy-related lineage plasticity, which may be relevant for other solid tumors.
2020-11-04 | PXD016861 | Pride
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
Project description:FOXA2/AP-1 drives prostate cancer lineage plasticity [RNA-seq]
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