Neuroendocrine prostate cancer (NEPC) is a highly aggressive form of prostate cancer that can develop in patients who have undergone hormonal therapies for prostate adenocarcinoma, either as a resistance mechanism (t-NEPC) or in rare cases as a new occurrence (de novo). Despite its severity, we still have a limited understanding of the clinical and molecular characteristics of NEPC.

Identifying the specific clinical and molecular traits associated with NEPC can significantly improve affected individuals' diagnosis, treatment strategies, and prognosis.

RNA sequencing is one of the most important tools in NEPC research. It enables comprehensive transcriptome analysis, revealing gene expression patterns specific to NEPC, thereby aiding in molecular subtyping, biomarker identification, and the discovery of therapeutic targets.

Here, we have compiled 5 datasets that have significantly advanced our understanding of NEPC's molecular landscape. Explore these interesting datasets about signatures to identify aggressive prostate cancer phenotypes, the implication of Neuropilin-2 in therapy resistance, the role of AR signaling in prostate neuroendocrine differentiation, etc.

You can find more highly curated datasets on NEPC (see figure below) that can be visualized and analyzed using our biomedical data platform, Polly.

‍Dataset 1

A Basal Stem Cell Signature Identifies Aggressive Prostate Cancer Phenotypes

Dataset ID: GSE82071_GPL11154
Year of Publication: 2016
Total Samples: 20
Experiment type: Bulk RNA sequencing
Organism: Homo sapiens
Reference link: Publication, Raw data

Summary:

Aggressive cancers and normal stem cells often share similar molecular and functional traits. It is unclear if aggressive prostate cancer phenotypes molecularly resemble normal stem cells within the human prostate. The researchers performed high-throughput RNA sequencing on uncultured, highly purified epithelial populations from human prostates obtained after radical prostatectomy from human prostates. They found the basal population to be defined by genes associated with developmental programs, epigenetic remodeling, and invasiveness.

They further generated a 91-gene basal signature and applied it to gene expression datasets from patients with organ-confined or castration-resistant, metastatic prostate cancer. Metastatic prostate cancer was more enriched for the basal stem cell signature than organ-confined prostate cancer. Moreover, histological subtypes within prostate cancer metastases varied in their enrichment of the stem cell signature, with small cell neuroendocrine carcinoma being the most stem cell-like. Bioinformatic analysis of the basal cell and two human small-cell gene signatures identified a set of E2F target genes common to all three signatures. These results suggest that the most aggressive variants of prostate cancer share a core transcriptional program with normal prostate basal stem cells.

Dataset 2

Neuropilin-2 axis in regulating the secretory phenotype of neuroendocrine-like prostate cancer cells: implication in therapy resistance

Dataset ID: GSE202299_GPL24676
Year of Publication: 2022
Total Samples: 2
Experiment type: Bulk RNA sequencing
Organism: Homo sapiens
Reference link: Publication, Raw data

Summary:

Gene expression was first compared between prostate adenocarcinoma cell line LNCaP C4-2 and our developed neuroendocrine-like derived cell line DKD (LNCaP C4-2 stably depleted with TP53 and RB1). In the next set, the authors compared the gene expression of neuroendocrine-like DKD under the presence and absence of Neurolipilin-2.

Dataset 3

Resistance to AR Signaling Inhibition Does Not Necessitate Prostate Neuroendocrine Differentiation

Dataset ID: GSE160393_GPL16791
Year of Publication: 2021
Total Samples: 62
Experiment type: Bulk RNA sequencing
Organism: Homo sapiens
Reference link: Publication, Raw data

Summary:

Resistance to 2nd generation androgen receptor (AR) signaling inhibitors (ARSi) occurs in a subset of metastatic castration-resistant prostate cancer (mCRPC) patients with the emergence of a neuroendocrine (NE) phenotype. This NE phenotype is typically accompanied by loss of AR expression coupled with mutations/deletions in PTEN, TP53, and/or RB1, in addition to overexpression of DNMTs, EZH2, and/or SOX2. A combination of cell and molecular biology analyses of 29 prostate cancer patient-derived xenografts (PDXs) recapitulating the full spectrum of proposed genetic alterations driving NE differentiation and CRISPR-Cas9 AR-knockout cells were utilized.

These analyses document that: 1) ARSi-resistance in mCRPC cells that lack AR expression in the context of a TP53 mutation and PTEN deletion does not necessitate acquiring a NE phenotype but alternatively can occur via the emergence of an AR-/NE- double negative (DN) cancer; 2) NE cancers lack AR expression due to transcriptional silencing via promoter hypermethylation; and 3) in contrast, the lack of AR expression in DN cancers is not due to promoter hypermethylation-dependent silencing. Regardless of their cell of origin, the prevalence of both AR-/NE- DN and AR-/NE+ ARSi-resistant cancers is increasing clinically, highlighting the urgent need to develop therapies that target vulnerabilities beyond AR pathway inhibition.

Dataset 4

ONECUT2 Drives Neuroendocrine Prostate Cancer Through Hypoxia Signaling

Dataset ID: GSE106305_GPL18573
Year of Publication: 2019
Total Samples: 28
Experiment type: Bulk RNA sequencing
Organism: Homo sapiens
Reference link: Publication, Raw data

Summary:
Neuroendocrine prostate cancer is characterized by loss of androgen receptor (AR) signaling during neuroendocrine transdifferentiation, which results in resistance to AR-targeted therapy. Clinically, genomically and epigenetically, NEPC resembles other types of poorly differentiated neuroendocrine tumors (NETs). Through pan-NET analyses, the authors identified ONECUT2 as a candidate master transcriptional regulator of poorly differentiated NETs. ONECUT2 ectopic expression in prostate adenocarcinoma synergizes with hypoxia to suppress androgen signaling and induce neuroendocrine plasticity.

ONEUCT2 drives tumor aggressiveness in NEPC, partially through regulating hypoxia signaling and tumor hypoxia. Specifically, ONECUT2 activates SMAD3, which regulates hypoxia signaling through modulating HIF1α chromatin-binding, leading NEPC to exhibit higher degrees of hypoxia compared to prostate adenocarcinomas. Treatment with hypoxia-activated prodrug TH-302 potently reduces NEPC tumor growth. Collectively, these results highlight the synergy between ONECUT2 and hypoxia in driving NEPC, and emphasize the potential of hypoxia-directed therapy for NEPC patients.

Dataset 5

Subtype Heterogeneity and Epigenetic Convergence in Neuroendocrine Prostate Cancer [RNA-seq]

Dataset ID: GSE156289_GPL18573
Year of Publication: 2021
Total Samples: 34
Experiment type: Bulk RNA sequencing
Organism: Homo sapiens
Reference link: Publication, Raw data

Summary:

Subtype heterogeneity and epigenetic convergence in NEPC. Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities. Here, the authors report the chromatin landscapes of a range of human NECs and show convergence to the activation of a common epigenetic program. With a particular focus on the treatment-emergent neuroendocrine prostate cancer (NEPC), they analyze cell lines, patient-derived xenograft (PDX) models, and human clinical samples to show the existence of two distinct NEPC subtypes based on the expression of the neuronal transcription factors ASCL1 and NEUROD1.

While these subtypes are mutually exclusive in cell lines and PDX models, single-cell analysis of human clinical samples exhibits a more complex tumor structure with subtypes coexisting as separate sub-populations within the same tumor. These tumor sub-populations differ genetically and epigenetically, contributing to intra- and inter-tumoral heterogeneity in human metastases. Overall, the results provide a deeper understanding of the shared clinicopathological characteristics shown by NECs. Furthermore, the intratumoral heterogeneity of human NEPCs suggests the requirement of simultaneous targeting of coexisting tumor populations as a therapeutic strategy.

‍

The structured and harmonized repositories on Polly allows complex queries and generate accurate search results on bulk and single-cell RNA-seq data. Accelerate your journey of finding relevant biomedical datasets, creating cohorts, and visualizing and analyzing the data, thereby deriving actionable insights and probable targets. Connect with us to know more!