Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Therapeutic Implications for Intrinsic Phenotype Classification of Metastatic Castration Resistant Prostate Cancer

ABSTRACT: Metastatic prostate cancers are recognized to exhibit subtypes categorized by underlying genomic alterations and phenotypes largely partitioned by androgen receptor signaling and neuroendocrine activity. In the present study we evaluated a phenotypic classification approach originally developed for subtyping breast carcinomas using the PAM50 gene signature. PAM50 subtypes associated with specific genotypes such as RB1 loss and phenotypes such as small cell/neuroendocrine carcinoma as well as tumor histology including cribriform morphology. In the context of clinical translation, PAM50 classification segregated tumors into groups with distinct druggable targets such as cell surface proteins amenable to antibody-drug-conjugates (ADCs). Classification into Luminal A, Luminal B and Basal tumors associated with time on androgen receptor signaling inhibitors, and responses to taxane chemotherapy. These findings support further clinical investigation of PAM50-based classification for prostate cancer patient stratification in therapeutic studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199596 | GEO | 2022/05/03

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

DPYSL5 is Highly Expressed in treatment-induced Neuroendocrine Prostate Cancer and Promotes Lineage Plasticity via EZH2/PRC2

Project description:Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer resistant to androgen receptor (AR) inhibitors. Our study unveils that AR suppresses neuronal development protein dihydropyrimidinase-related protein 5 (DPYSL5), providing a mechanism for neuroendocrine transformation under androgen deprivation therapy. Our unique CRPC-NEPC cohort with 157 patient samples, including 55 t-NEPC patient samples, shows a high expression of DPYSL5 in t-NEPC patients, and that DPYSL5 correlates with neuroendocrine markers and inversely with AR and PSA. DPYSL5 overexpression in prostate cancer cells induces neuron like phenotype, enhances invasion, proliferation, and upregulates stemness and neuroendocrine related markers. Mechanistically, DPYSL5 promotes prostate cancer cell plasticity via EZH2-mediated PRC2 activation. Depletion of DPYSL5 halts proliferation, induces G1 phase cell cycle arrest, reverses neuroendocrine phenotype and upregulates luminal genes. In conclusion, DPYSL5 plays a critical role in regulating prostate cancer cell plasticity, and we propose the AR/DPYSL5/EZH2/PRC2 axis as a novel driver of t-NEPC progression.

2024-01-02 | GSE151433 | GEO

Proteomic analysis of archival breast cancer clinical specimens identifies biological subtypes with distinct survival outcomes

Project description:Despite the advancement of genomic classification of breast cancer, current clinical tests and treatment decisions are commonly based on protein level information. Formalin-fixed paraffin-embedded (FFPE) tissue specimens are widely available and can be directly linked to extended clinical outcomes. We performed comprehensive proteomic profiling of 300 FFPE breast cancer surgical specimens, 75 of each PAM50 subtype, with linked clinical outcomes. Using our highly sensitive SP3-Clinical Tissue Proteomics platform, we quantified 4214 proteins across all 300 samples. The analysis identified a distinct proteomic group characterized by high expression of immune response proteins and favorable survival rates. Four clinically distinct proteomic clusters within samples classified as triple negative breast cancer by immunohistochemistry had features of “basal-immune hot”, “basal-immune cold”, “mesenchymal”, and “luminal androgen receptor”. Our proteomic analysis characterizes the heterogeneity of breast cancer in a clinically-applicable manner, identifies potential biomarkers and therapeutic targets, and provides a resource for clinical breast cancer classification.

2022-02-22 | PXD024322 | Pride

Targeting the fibroblast growth factor pathway in molecular subtypes of castration-resistant prostate cancer

Project description:Androgen receptor (AR) pathway inhibition remains the cornerstone for first- and second-line prostate cancer therapies. Although AR signaling inhibitors, such as enzalutamide and abiraterone extend survival in recurrent and castration-resistant prostate cancer (CRPC), durable and complete responses are rare. Resistance mechanisms employed by metastatic CRPC include amplification of AR and AR splice variants in AR-positive CRPC (ARPC) and conversion to AR-null phenotypes, such as double-negative prostate cancer (DNPC) and small cell or neuroendocrine prostate cancer (SCNPC). We have shown previously that DNPC can bypass AR-dependence through fibroblast growth factor (FGF) signaling. However, the role of the fibroblast growth factor receptor (FGFR) pathway in other molecular subtypes of CRPC has not been elucidated.

2023-09-19 | GSE228283 | GEO

Notch signaling suppresses neuroendocrine differentiation and alters the tumor immune microenvironment in advanced prostate cancer

Project description:Neuroendocrine prostate cancer (NEPC) is an aggressive, androgen-independent variant of prostate cancer (PCa) that most commonly develops in patients as a mechanism of therapeutic resistance. The underlying mechanisms driving PCa lineage plasticity and trans-differentiation to a neuroendocrine lineage are not fully understood. Here, we identify Notch signaling as a key suppressor of neuroendocrine differentiation in PCa. Restoration of Notch signaling in NEPC models results in phenotypic conversion towards a non-neuroendocrine state with expression of prostate luminal cell markers and immunologic changes including up-regulation of MHC Class I and II and type I interferon signaling that correlate with changes in the tumor immune microenvironment. Overall, these data provide new insights into how Notch signaling influences PCa lineage plasticity and points to new therapeutic avenues to modulate it.

2024-08-01 | GSE235036 | GEO

Notch signaling suppresses neuroendocrine differentiation and alters the tumor immune microenvironment in advanced prostate cancer

2024-08-28 | GSE234819 | GEO

Integrative epigenetic taxonomy of primary prostate cancer [ChIP-Seq]

Project description:The Androgen Receptor (AR) is the key-driving transcription factor in prostate cancer, tightly controlled by epigenetic regulation. To date, most epigenetic profiling has been performed in cell lines or limited tissue samples. To comprehensively study the epigenetic landscape, we complemented RNA-seq with ChIP-seq for AR and histone modification marks (H3K27ac, H3K4me3, H3K27me3) in 100 primary prostate carcinomas. Integrative molecular subtyping of the five data streams revealed three major subtypes of which two were clearly TMPRSS2-ERG dictated. Importantly, a third novel subtype was identified, with low AR chromatin binding and activity, even though the receptor was clearly expressed. While positive for neuroendocrine-hallmark genes, these tumors were copy number-neutral with low mutation burden, significantly depleted for genes characteristic of poor-outcome associated luminal B-subtype. We present a rich novel resource on transcriptional and epigenetic control in prostate cancer, revealing a tight control of gene regulation differentially dictated by AR over the three subtypes.

2018-10-03 | GSE120738 | GEO

Integrative epigenetic taxonomy of primary prostate cancer [RNA-Seq]

2018-10-03 | GSE120741 | GEO

A Basal Stem Cell Signature Identifies Aggressive Prostate Cancer Phenotypes

Project description:Aggressive cancers and normal stem cells often share similar molecular and functional traits. It is unclear if aggressive phenotypes of prostate cancer molecularly resemble normal stem cells residing within the human prostate. We performed high-throughput RNA sequencing on uncultured, highly purified epithelial populations from human prostates obtained after radical prostatectomy. We found the basal population to be defined by genes associated with developmental programs, epigenetic remodeling, and invasiveness. We 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. Transcriptional analysis of 10 uncultured prostatic basal and luminal populations from either the benign or malignant prostate tissue of 8 human prostate cancer patients by high-throughput RNA-seq

2016-06-01 | E-GEOD-82071 | biostudies-arrayexpress

ASCL1 activates neuronal stem cell-like lineage programing through remodeling of the chromatin landscape in prostate cancer [RNA-Seq]

Project description:Treatment with androgen receptor pathway inhibitors (ARPIs) in prostate cancer leads to the emergence of resistant tumors characterized by lineage plasticity and divergent differentiation toward neuroendocrine lineage. We found that ARPIs induce a rapid epigenetic alteration mediated by large-scale chromatin remodeling to support activation of stem/neuronal transcriptional programs. We identified motifs for the proneuronal transcription factor ASCL1 to be enriched in hyper-accessible regions. ASCL1 acts as a driver of the lineage plastic, neuronal transcriptional program to support treatment resistance and neuroendocrine phenotype. Targeting ASCL1 switches the neuroendocrine lineage back to the luminal epithelial state. This effect is modulated by disruption of the polycomb repressive complex-2 and change the chromatin architecture in favor of luminal phenotype. Our study provides insights into the epigenetic alterations induced by ARPI governed by ASCL1, provides a proof of principle of targeting ASCL1 to reverse the neuroendocrine phenotype, support luminal conversion and re-addiction to ARPIs.

2022-03-30 | GSE183199 | GEO

ASCL1 activates neuronal stem cell-like lineage programing through remodeling of the chromatin landscape in prostate cancer [ChIP-Seq]

2022-03-30 | GSE183198 | GEO