Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

RNA-Seq of Primary and Recurrent DSRCT Tumors

ABSTRACT: Desmoplastic small round cell tumor (DSRCT) is a rare pediatric cancer caused by the EWSR1-WT1 fusion oncogene. Despite initial response to chemotherapy, DSRCT has a recurrence rate of over 80% leading to poor patient prognosis with a 5-year survival rate of only 15-25%. Owing to the rarity of DSRCT, sample scarcity is a barrier to understanding DSRCT biology and developing effective therapies. Here, we performed RNA-sequencing on a novel pair of primary and recurrent DSRCT tumors harvested from the same patient 5-years apart. To gain insights into gene expression alterations associated with recurrence, we performed pathway analysis on Gene Ontology Biological Processes and KEGG pathways. Upregulated pathways in the recurrent tumor included DNA repair and mRNA splicing related pathways, while downregulated pathways included immune system function and focal adhesion. We further examined the expression of previously identified EWSR1-WT1 regulated targets, a large number of which were enriched in the recurrent tumor. Overall, this study provides novel understanding of DSRCT biology and a new RNA-seq data set to advance future studies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230603 | GEO | 2023/07/19

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

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

Project description: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.

2024-02-06 | GSE252051 | GEO

Genome-wide AR and H3K27Ac binding profiles in DSRCT cells, xenograft and PDX mouse tumors

Project description:DSRCT is an aggressive, often fatal, sarcoma subtype that usually present in post-pubertal adolescents and young adults. Though the pathognomonic EWSR1-WT1 fusion protein is responsible for tumorigenesis, the androgen receptor (AR) has been suggested as a key contributor to tumor survival and growth. Reverse-phase protein lysate arrays (RPPA) were used to identify new drug targets in DSRCT not present in Ewing sarcoma, a close molecular cousin that shares an EWSR1 N-terminus chimeric partner. Among the 151 proteins analyzed, the AR protein was the most differentially expressed protein, which led to follow-on studies to investigate its role in DSRCT survival and growth in cell lines, xenografts, and patient-derived tumor explants (PDXs), which retain the best fidelity to their human tumor counterparts. Modern-day 2nd-generation AR antagonists were tested for preclinical antitumor activity, in addition to novel AR-directed antisense oligonucleotides that rapidly suppress post-transcriptional activity. Our research demonstrates an important role for the AR in promoting tumor growth and survival in preclinical DSRCT models. Given the widespread availability of safe, orally administered FDA-approved agents used for prostate cancer, such as abiraterone or enzalutamide that potently block AR steroidogenesis or intracellular AR signaling, one could quickly evaluate their effect in DSRCT in phase 2 trials.

2022-06-21 | GSE151380 | GEO

N3 induced reprogramming and ShWT1 knock-down in DSRCT cell lines

Project description:The object of this study is to identify the molecular signature underlying the therapeutic potential of N3-induced growth arrest in Desmoplastic Small Round Cell Tumor (DSRCT). The molecular hallmark of DSRCT is the EWS-WT1 fusion protein formed by chromosomal translocations found in DSRCT. The N-terminal transactivation domain of EWS is fused to the C-terminal DNA binding domain of WT1, creating an oncogenic transcription factor. We have recently discovered that addition of N3 supplement to growing DSRCT cells leads to a rapid cessation of cell growth.

2022-04-14 | GSE180031 | 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 [scRNA-Seq]

2024-04-15 | GSE263521 | GEO

Proteomic Comparison Of DSRCT, Normal Mesenteric Tissues and ES

Project description:Desmoplastic small round cell tumor (DSRCT) is an aggressive malignancy that occurs predominantly in young adult males and is characterized by abdominopelvic sarcomatosis exhibiting multi-lineage cellular nests of epithelial, muscular, mesenchymal, and neural differentiation admixed with desmoplastic stroma. Prior to the recognition of the disease as a distinct clinical entity, DSRCT was invariably misclassified as poorly differentiated atypical cancer of the testes, ovary, mesentery, or gastrointestinal tract, and the chemotherapies used for those malignancies elicited poor clinical response. As previously reported, a tectonic shift in the treatment of these patients occurred after researchers made two astute observations: 1) DSRCT microscopically resembles other small round “blue cell” sarcoma subtypes (e.g., ES, rhabdomyosarcoma, synovial sarcoma), and 2) DSRCT and ES have the same N-terminal EWSR1 fusion partner. Proteomic analysis using a reverse-phase protein lysate array (RPPA) was used to elucidate biomarkers that distinguish DSRCT from adjacent normal tissue and Ewing sarcoma. This proteomic analysis revealed novel proteins, such as the androgen receptor and Syk, that may be susceptible to drug targeting, as well as oncogenic pathways like Akt-PI3K that are highly expressed in DSRCT.

2020-12-31 | GSE108687 | GEO

Transcriptomic Analysis Identifies B-Lymphocyte Kinase as a Therapeutic Target for Desmoplastic Small Round Cell Tumor Cancer Stem Cell-Like Cells [scRNA-seq]

Project description:Desmoplastic Small Round Cell Tumor (DSRCT) is an aggressive pediatric cancer caused by the EWSR1-WT1 fusion oncoprotein. The tumor is refractory to treatment with a 5-year survival rate of only 15-25%, necessitating the development of novel therapeutics, especially those able to target chemoresistant subpopulations. Novel in vitro cancer stem cell-like (CSC-like) culture conditions increase the expression of stemness markers (SOX2, NANOG) and reduce DSRCT cell line susceptibility to chemotherapy, while maintaining the ability of DSRCT cells to form xenografts. To gain insights into this chemoresistant model, RNA-seq was performed to elucidate transcriptional alterations between DSRCT cells grown in CSC-like spheres and normal 2-dimensional adherent state. Commonly upregulated and downregulated genes were identified and utilized in pathway analysis revealing upregulation of pathways related to chromatin assembly and disassembly and downregulation of pathways including cell junction assembly and extracellular matrix organization. Alterations in chromatin assembly suggest a role for epigenetics in the DSRCT CSC-like state which was further investigated with ATAC-seq, identifying over 10,000 differentially accessible peaks including 4,444 sphere accessible peaks and 6,120 adherent accessible peaks. Accessible regions were associated with higher gene expression including increased accessibility of the CSC marker SOX2 in CSC-like culture conditions. These analyses were further utilized to identify potential CSC therapeutic targets, leading to the identification of B-lymphocyte kinase (BLK) as a CSC-enriched, EWSR1-WT1 regulated, druggable target. BLK inhibition and knockdown reduced CSC-like properties including abrogation of tumorsphere formation and stemness marker expression. Importantly, BLK knockdown reduced DSRCT CSC-like cell chemoresistance making its inhibition a promising target for future combination therapy.

2023-12-01 | GSE248856 | GEO

Transcriptomic Analysis Identifies B-Lymphocyte Kinase as a Therapeutic Target for Desmoplastic Small Round Cell Tumor Cancer Stem Cell-Like Cells [RNA-seq]

2023-12-01 | GSE248761 | GEO

Transcriptomic Analysis Identifies B-Lymphocyte Kinase as a Therapeutic Target for Desmoplastic Small Round Cell Tumor Cancer Stem Cell-Like Cells [ATAC-seq]

2023-12-01 | GSE248758 | GEO

DSRCT RNA genomic sequencing

Project description:Purpose: To further understand the molecular pathogenesis of desmoplastic small round cell tumor (DSRCT), a rare but often fatal malignancy occurring primarily in young males, we used next-generation RNA sequencing to investigate the gene expression profiles intrinsic to this disease.Experimental Design: RNA from DSRCT tumor samples were obtained from the Cooperative Human Tissue Network biorepository. RNA sequencing was completed using the Illumina HiSeq 2000 system. Presence of the EWSR1-WT1 fusion was verified using both RNA-sequencing and PCR. Validation studies, including WT1 ChIP-seq, RNA sequencing, and EWS-WT1 knockdown experiments, were performed on an established DSRCT cell line, JN-DSRCT-1. Protein expression of clinically relevant genes determined by RNA sequencing was confirmed using immunohistochemistry. A panel of immune signature genes was also evaluated to identify possible immune therapeutic targets. Results: We analyzed the RNA from 14 tumor samples, of which two were confirmed negative for the diagnostic EWSR1-WT1 translocation. Principal component analysis of the sequencing data indicated that fusion-negative and fusion-positive tumors are transcriptionally distinct entities. Overlapping the significant ChIP-seq peaks with genes found to be highly expressed in the RNA sequencing data revealed that IGF2 and FGFR4 were both highly expressed, and targets of the EWS-WT1 fusion gene. This finding has potential clinical relevance for targeted therapeutic intervention. In addition, we identified the immune checkpoints CD200 and CD276 as potentially targetable genes whose expression is independent of the EWS-WT1 fusion gene in vitro.Conclusions: Despite the transcriptional complexity of this disease, we were able to identify IGF2, FGFR4, CD200, and CD276 as potential therapeutic targets for patients suffering from DSRCT.

| EGAS00001002770 | EGA

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data