Similar Datasets
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.
| S-EPMC6715370 | biostudies-literature
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
| PRJNA481735 | ENA
Project description:N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer [RNA-seq]
| PRJNA481738 | ENA
Project description:N-Myc-mediated epigenetic reprogramming drives lineage plasticity in advanced prostate cancer [ChIP-seq]
| PRJNA481737 | ENA
Project description:PlexinD1 is an axon guidance molecule which is upregulated in neuroendocrine prostate cancer (PC). In order to better understand its role in mediating the development and disease progression in PC, we performed the RNA-seq in PC cells in lack of or with enforced PlexinD1 expression comparing to the control cells. We compared the gene expression profile and conducted downstream pathway analysis. Our data dememstrated that PlexinD1 regulates the cell lineage in castration-resistant PC by activating Gli1 signaling.
2024-12-02 | GSE253766 | GEO
Project description:PlexinD1 drives the lineage plasticity in advanced prostate cancer
| PRJNA1067089 | ENA
Project description:The androgen receptor (AR) signaling pathway is critical for growth and differentiation of prostate cancer cells. For that reason, androgen deprivation therapy with medical or surgical castration is the principal treatment for metastatic prostate cancer. More recently, new potent AR signaling inhibitors (ARSIs) have been developed. These drugs improve survival for men with metastatic castration-resistant prostate cancer (CRPC), the lethal form of the disease. However, ARSI resistance is nearly universal. One recently appreciated resistance mechanism is lineage plasticity or switch from an AR-driven, luminal differentiation program to an alternate differentiation program. Importantly, lineage plasticity appears to be increasing in incidence in the era of new ARSIs, strongly implicating AR suppression in this process. Lineage plasticity and shift from AR-driven tumors occur on a continuum, ranging from AR-expressing tumors with low AR activity to AR-null tumors that have activation of alternate differentiation programs versus the canonical luminal program found in AR-driven tumors. In many cases, AR loss coincides with the activation of a neuronal program, most commonly exemplified as therapy-induced neuroendocrine prostate cancer (t-NEPC). While genetic events clearly contribute to prostate cancer lineage plasticity, it is also clear that epigenetic events-including chromatin modifications and DNA methylation-play a major role. Many epigenetic factors are now targetable with drugs, establishing the importance of clarifying critical epigenetic factors that promote lineage plasticity. Furthermore, epigenetic marks are readily measurable, demonstrating the importance of clarifying which measurements will help to identify tumors that have undergone or are at risk of undergoing lineage plasticity. In this review, we discuss the role of AR pathway loss and activation of a neuronal differentiation program as key contributors to t-NEPC lineage plasticity. We also discuss new epigenetic therapeutic strategies to reverse lineage plasticity, including those that have recently entered clinical trials.
| S-EPMC9329809 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-09-09 | GSE137072 | GEO