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GSE49967
Homo sapiens
11 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Though p53 mutations are rare in Ewing sarcoma, there is a strong indication that p53-mutant tumors form a particularly bad prognosis group. As such, novel treatment strategies are warranted that would specifically target and eradicate tumor cells containing mutant-p53 in this subset of ES patients.
Publication Title
Variability in functional p53 reactivation by PRIMA-1(Met)/APR-246 in Ewing sarcoma.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 11 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Transient transfection of a Ewing's Sarcoma cell line expressing type I EWS-FLI1 fusion and doxycycline-inducible short hairpin RNA against EWS-FLI1 (A673sh)
Publication Title
Suppression of FOXO1 is responsible for a growth regulatory repressive transcriptional sub-signature of EWS-FLI1 in Ewing sarcoma.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 10 Downloadable Samples
Illumina HiSeq 2000
Description
MicroRNAs serve to fine-tune gene expression and play an important regulatory role in tissue specific gene networks. The identification and validation of miRNA target genes in a tissue still poses a significant problem since the presence of a seed sequence in the 3´UTR of an mRNA and its expression modulation upon ectopic expression of the miRNA do not reliably predict regulation under physiological conditions. The chimeric oncoprotein EWS-FLI1 is the driving pathogenic force in Ewing Sarcoma. miR-17-92, one of the most potent oncogenic miRNAs, was recently reported to be the top EWS-FLI1 activated miRNA. Using a combination of AGO2 pull-down experiments by PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) and of RNAseq upon miRNA depletion by ectopic sponge expression, we aimed to identify the targetome of miR-17-92 in Ewing sarcoma. Intersecting both datasets we found an enrichment of PAR-CLIP hits for members of the miR-17-92 cluster in the 3´UTRs of genes up-regulated in response to mir-17-92 specific sponge expression. Strikingly, approximately a quarter of these genes annotate to the TGFB/BMP pathway, the majority mapping downstream of SMAD signalling. Taken together, our findings shed light on the complex miRegulatory landscape of Ewing Sarcoma pointing miR-17-92 as a key node connected to TGFB/BMP pathway Overall design: mRNA profiles of a Ewings Sarcoma cellline (clone of A673 with inducible sh EWS-FLI1 knockdown) treated with microRNA sponges and controls
Publication Title
The role of miR-17-92 in the miRegulatory landscape of Ewing sarcoma.
Sample Metadata Fields
Cell line, Treatment, Subject
View Samples- Homo sapiens
- 74 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Affymetrix exon array data were generated from total RNA that was isolated from localized Ewing sarcoma biopsy specimens. Expression of transcript summarized data was compared to data generated from normal stem cells and normal adult tissues.
Publication Title
Overexpression of HOX genes is prevalent in Ewing sarcoma and is associated with altered epigenetic regulation of developmental transcription programs.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 32 Downloadable Samples
- Illumina HiSeq 2000
Description
Ewing Sarcoma (EwS) is a EWS-FLI1- fusion driven pediatric bone cancer with high metastatic potential. Cellular plasticity, typically regulated via the Rho-pathway, is a prerequisite for metastasis initiation. Here we interrogated the role of the Rho transcriptional effectors MRTFA/B in EwS. We find MRTFB transcriptional function strongly repressed by EWS-FLI1. Under EWS-FLI1-low (knock-down) conditions, MRTFB is activated and antagonizes global EWS-FLI1-dependent transcription. Furthermore, ChIP-Seq revealed strong overlaps in MRTFB and EWS-FLI1 chromatin occupation, especially for EWS-FLI1 suppressed-(anticorrelated) genes. Enrichment of TEAD binding motifs in these shared genomic binding regions, and overlapping transcriptional footprints of MRTFB and TEAD1-4 perturbation led us to propose synergy between MRTFB and TEAD in the regulation of EWS-FLI1 suppressed-anticorrelated genes. Finally, we find F-actin assembly to be already perturbed in our EwS model, F-actin polymerization is perturbed by EWS-FLI1 in our model cell line, however,but pharmacological inhibition of actin polymerization still reduced expression serum-induced expression of MRTFB/YAP-1/TEAD target genes. In summary our data support a model of indirect and direct EWS-FLI1-driven perturbation of MRTFB/YAP-1/TEAD target gene regulation . Overall design: 1. Transient si-RNA mediated knockdown of MRTFA (MKL-1), MRTFB (MKL-2) and doxycyline-induced EWS-FLI1 knockdown in A673/TR/shEF EwS cells (8 samples/replicate: 2 replicates total); 2. Combined transient knockdown of MRTFA, MRTFB and EWS-FLI1 in SK-N-MC EwS cells (4 samples/replicate: 2 replicates total); 3. Combined knockdown of TEAD1-4 by pooling si-RNA against TEAD1, TEAD2, TEAD3 and TEAD 4 combined with doxycycline-inducible EWS-FLI1 knockdown (4 samples/replicate: 8 samples total)
Publication Title
EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma.
Sample Metadata Fields
Cell line, Treatment, Subject
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Ewing Sarcoma (EwS) is a EWS-FLI1- fusion driven pediatric bone cancer with high metastatic potential. Cellular plasticity, typically regulated via the Rho-pathway, is a prerequisite for metastasis initiation. Here we interrogated the role of the Rho transcriptional effectors MRTFA/B in EwS. We find MRTFB transcriptional function strongly repressed by EWS-FLI1. Under EWS-FLI1-low (knock-down) conditions, MRTFB is activated and antagonizes global EWS-FLI1-dependent transcription. Furthermore, ChIP-Seq revealed strong overlaps in MRTFB and EWS-FLI1 chromatin occupation, especially for EWS-FLI1 suppressed-(anticorrelated) genes. Enrichment of TEAD binding motifs in these shared genomic binding regions, and overlapping transcriptional footprints of MRTFB and TEAD1-4 perturbation led us to propose synergy between MRTFB and TEAD in the regulation of EWS-FLI1 suppressed-anticorrelated genes. Finally, we find F-actin assembly to be already perturbed in our EwS model, F-actin polymerization is perturbed by EWS-FLI1 in our model cell line, however,but pharmacological inhibition of actin polymerization still reduced expression serum-induced expression of MRTFB/YAP-1/TEAD target genes. In summary our data support a model of indirect and direct EWS-FLI1-driven perturbation of MRTFB/YAP-1/TEAD target gene regulation .
Publication Title
EWS-FLI1 perturbs MRTFB/YAP-1/TEAD target gene regulation inhibiting cytoskeletal autoregulatory feedback in Ewing sarcoma.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Translocations of ETS transcription factors are driver mutations in diverse cancers. We investigated the genomic network of the ETS fusion EWS/FLI1 in Ewing's sarcoma (ESFT) as a model of ETS-driven tumorigenesis. ChIP-Seq and transcriptional analysis identified E2F3 as a principle co-factor of EWSFLI1 defining functionally distinct gene sets. While EWS/FLI1 binding independent of E2F3 predominantly associated with repressed differentiation genes, significant co-localization with E2F3 was discovered at proximal promoters of activated growth-related genes. Thus, EWS/FLI1 promotes oncogenesis by simultaneously perturbing differentiation state and augmenting the expression of genes co-regulated by E2F3. Integration of additional E2F3 and ERG localization data from prostate cancer containing TMPRSS2/ERG verified that the ETS-E2F module is also found in prostate cancer and may be of general relevance to ETS driven cancers.
Publication Title
Oncogenic ETS fusions deregulate E2F3 target genes in Ewing sarcoma and prostate cancer.
Sample Metadata Fields
Disease, Cell line, Treatment, Time
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Expression profiles were generated from hESC-derived neural crest stem cells following transduction with GFP control vector or EWS-FLI1 vector. Expression was analyzed in stem cell conditions 5 days after transduction (undifferentiated conditions) and after 6 weeks in differentiation media (differentiation conditions).
Publication Title
Overexpression of HOX genes is prevalent in Ewing sarcoma and is associated with altered epigenetic regulation of developmental transcription programs.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Hypoxia is an important condition in the tumor cell microenvironment and approximately 1-1.5% of the genome is transcriptionally responsive to hypoxia with hypoxia-inducible factor-1 (HIF-1) as a major mediator of transcriptional activation. Tumor hypoxia is associated with a more aggressive phenotype of many cancers in adults, but data on pediatric tumors are scarce. By immunohistochemical analysis, HIF-1 expression was readily detectable in 18/28 primary Ewings sarcoma family tumors (ESFT), a group of highly malignant bone-associated tumors in children and young adults, which encouraged us to study the effect of hypoxia on ESFT cell lines in vitro.
Publication Title
Hypoxia modulates EWS-FLI1 transcriptional signature and enhances the malignant properties of Ewing's sarcoma cells in vitro.
Sample Metadata Fields
Disease, Cell line
View Samples