Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Comprehensive Transcriptomic Analysis of EWSR1::WT1 Targets Identifies CDK4/6 Inhibitors as a Novel Therapeutic for Desmoplastic Small Round Cell Tumor

ABSTRACT: Desmoplastic small round cell tumor (DSRCT) is an aggressive, pediatric tumor characterized by the EWSR1::WT1 oncogene. Targeted therapies have not been developed and multimodal therapy is insufficient, leading to a 5-year survival rate of only 15-25%. Here, we deplete EWSR1::WT1 in DSRCT and for the first time establish its essentiality in vivo. Through transcriptomic analysis, we discover novel mechanistic insights into EWSR1::WT1 functionality including the uniqueness of its transcriptional alterations, the direct role of EWSR1::WT1 binding in gene upregulation, and the dominant role of the one of its two isoforms in transcription. We show that the dominant isoform binds to the CCND1 promoter and stimulates DSRCT growth through the Cyclin D-CDK4/6-RB axis. Treatment with the CDK4/6 inhibitor palbociclib successfully reduced growth in two DSRCT xenograft models. Given palbociclib’s previous approval by the FDA for the treatment of breast cancer, we advance palbociclib as an exciting DSRCT therapy that warrants urgent clinical investigation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE252051 | GEO | 2024/02/06

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors.

Project description:EWS fusion oncoproteins underlie the pathogenesis of several human malignancies including Desmoplastic Small Round Cell Tumor (DSRCT), an aggressive mesenchymal tumor driven by fusions between the disordered domain of EWS and the developmental transcription factor WT1. Here we combined chromatin occupancy and long-range interaction profiles to identify EWS-WT1-dependent gene regulation networks and directly controlled target genes. We show that EWS-WT1 operates primarily as a powerful activator of distal regulatory elements and controls an oncogenic gene expression program that characterize primary DSRCTs. Moreover, EWS-WT1 has two isoforms that differ by three amino acids in their DNA binding domain (+/- KTS), as observed for wild type WT1, and we show that each fusion isoform has a specific DNA binding profile that is distinct from its wild type counterparts and requires a functional EWSR1 prion like domain. Remarkably, xenograft experiments using human mesothelial cells, candidate cells of origin of DSRCT, reveal that both isoforms are required to generate viable tumors that resemble DSRCT. Finally, we identify new candidate EWS-WT1 target genes with potential therapeutic implications, including CCND1, whose inhibition by the clinically-approved drug Palbociclib leads to marked tumor burden decrease in DSRCT PDXs in vivo. Taken together, our studies identify gene regulation programs and therapeutic vulnerabilities in DSRCT and provide a mechanistic understanding of the complex isoform-dependent oncogenic activity of EWS-WT1.

2024-10-01 | GSE248842 | GEO

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors [HiChIP]

2023-10-04 | GSE212978 | GEO

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors [Hi-C]

2023-10-04 | GSE242863 | GEO

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors [ChIP-seq]

2023-10-04 | GSE212977 | GEO

EWS-WT1 fusion isoforms establish oncogenic programs and therapeutic vulnerabilities in Desmoplastic Small Round Cell Tumors [RNA-seq]

2023-10-04 | GSE212976 | GEO

Desmoplastic small round cell tumor is dependent on EWS-WT1

Project description:Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft tissue malignancy. The disease is defined by the oncogenic EWS-WT1 transcription factor. However, the dependence of the tumor on this target has not been well-established and no EWS-WT1 targeted therapy has translated to the clinic. In this report we establish the dependence of DSRCT on EWS-WT1 as well as define a gene signature and a comprehensive list of downstream targets. The selective silencing of EWS-WT1 leads to the marked suppression of proliferation of both JN-DSRCT1 and BER cells. Loss of the fusion protein results in morphologic changes in the cells and eventual cellular apoptosis. RNA sequencing demonstrates large scale gene expression changes attributable to EWS-WT1 with several hundred induced or repressed downstream targets of the fusion. We conclude DSRCT is dependent on the EWS-WT1 transcription factor for cell survival. The presence of EWS-WT1 leads to enrichment of genes involved in aberrant cell differentiation and development as well as those involved in tumor metastasis.

2020-05-04 | GSE137561 | GEO

Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in Desmoplastic Small Round Cell Tumors [snMultiome]

Project description:Desmoplastic Small Round Cell Tumor (DSRCT) is a rare, aggressive sarcoma driven by the EWSR1-WT1 chimeric transcription factor. Despite this unique oncogenic driver, DSRCT displays a polyphenotypic differentiation of unknown causality. Using single-cell multi-omics on samples from patients, we find that DSRCT tumor cells cluster into consistant subpopulations with partially overlapping lineage- and metabolism-related transcriptional programs.

2024-04-15 | GSE263522 | GEO

Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in Desmoplastic Small Round Cell Tumors [ATAC-seq]

2024-05-22 | GSE267807 | GEO

Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in Desmoplastic Small Round Cell Tumors [Patient_bulkRNA-seq]

2024-05-22 | GSE267805 | GEO

Single-cell multiomics profiling reveals heterogeneous transcriptional programs and microenvironment in Desmoplastic Small Round Cell Tumors [Cell_line_RNA-seq]

2024-05-22 | GSE267804 | GEO