Single-cell analysis supports a luminal-neuroendocrine transdifferentiation in human prostate cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA573608 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10162346_1.fastq.gz | Fastqsanger.gz | |||
| SRR10162346_2.fastq.gz | Fastqsanger.gz | |||
| SRR10162347_1.fastq.gz | Fastqsanger.gz | |||
| SRR10162347_2.fastq.gz | Fastqsanger.gz | |||
| SRR10162348_1.fastq.gz | Fastqsanger.gz |
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Project description:Neuroendocrine prostate cancer (NEPC) is a subset of castration-resistant prostate cancer (CRPC) and is thought to derive from prostate adenocarcinoma. However, the cellular basis responsible for Neuroendocrine differentiation (NED) is still under debate. Here, we characterized the tumor cell diversity of 6 CRPC patients using single cell RNA sequencing (scRNA-seq) and detected NED in four patients.
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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.
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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: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:Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor. Although much progress has been made in understanding the development of neuroendocrine prostate cancer, the cellular architecture associated with neuroendocrine differentiation in human prostate cancer remain incompletely understood. Here, we use single-cell RNA sequencing to profile the transcriptomes of 21,292 cells from needle biopsies of 6 castration-resistant prostate cancers. Our analyses reveal that all neuroendocrine tumor cells display a luminal-like epithelial phenotype. In particular, lineage trajectory analysis suggests that focal neuroendocrine differentiation exclusively originate from luminal-like malignant cells rather than basal compartment. Further tissue microarray analysis validates the generality of the luminal phenotype of neuroendocrine cells. Moreover, we uncover neuroendocrine differentiation-associated gene signatures that may help us to further explore other intrinsic molecular mechanisms deriving neuroendocrine prostate cancer. In summary, our single-cell study provides direct evidence into the cellular states underlying neuroendocrine transdifferentiation in human prostate cancer.
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Project description:Double-negative prostate cancer (DNPC), characterized by AR-null tumors with inherent plasticity, predominantly arises following androgen deprivation therapy (ADT). However, the cellular origin, signaling hierarchy, and treatment strategies for this lethal subtype remain unclear. Here, we demonstrate that the loss of KMT2C, a histone H3K4 methylation transferase preferentially mutated in the DNPC subtype, collaborates with ADT to drive the transformation of luminal tumors into DNPC. Our findings reveal that DNPC arises from the transdifferentiation of luminal cells rather than basal cell expansion. This transdifferentiation is orchestrated by the upregulation of ΔNp63, induced by the dual inactivation of AR and KMT2C. Treatment with antiandrogens facilitates KMT2C binding to the enhancers of a subset of AR-regulated genes, compensating for AR inactivation to preserve the luminal identity. Among these, ARPP2 maintains its expression via KMT2C-dependent enhancer-promoter communication following AR inactivation.
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Project description:Double-negative prostate cancer (DNPC), characterized by AR-null tumors with inherent plasticity, predominantly arises following androgen deprivation therapy (ADT). However, the cellular origin, signaling hierarchy, and treatment strategies for this lethal subtype remain unclear. Here, we demonstrate that the loss of KMT2C, a histone H3K4 methylation transferase preferentially mutated in the DNPC subtype, collaborates with ADT to drive the transformation of luminal tumors into DNPC. Our findings reveal that DNPC arises from the transdifferentiation of luminal cells rather than basal cell expansion. This transdifferentiation is orchestrated by the upregulation of ΔNp63, induced by the dual inactivation of AR and KMT2C. Treatment with antiandrogens facilitates KMT2C binding to the enhancers of a subset of AR-regulated genes, compensating for AR inactivation to preserve the luminal identity. Among these, ARPP2 maintains its expression via KMT2C-dependent enhancer-promoter communication following AR inactivation.
2025-02-27 | GSE267773 | GEO
Project description:Double-negative prostate cancer (DNPC), characterized by AR-null tumors with inherent plasticity, predominantly arises following androgen deprivation therapy (ADT). However, the cellular origin, signaling hierarchy, and treatment strategies for this lethal subtype remain unclear. Here, we demonstrate that the loss of KMT2C, a histone H3K4 methylation transferase preferentially mutated in the DNPC subtype, collaborates with ADT to drive the transformation of luminal tumors into DNPC. Our findings reveal that DNPC arises from the transdifferentiation of luminal cells rather than basal cell expansion. This transdifferentiation is orchestrated by the upregulation of ΔNp63, induced by the dual inactivation of AR and KMT2C. Treatment with antiandrogens facilitates KMT2C binding to the enhancers of a subset of AR-regulated genes, compensating for AR inactivation to preserve the luminal identity. Among these, ARPP2 maintains its expression via KMT2C-dependent enhancer-promoter communication following AR inactivation.
2025-02-27 | GSE267771 | 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.
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