Wnt/beta-catenin activated Ewing sarcoma cells promote the angiogenic switch
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA512292 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8381990.fastq.gz | Fastqsanger.gz | |||
| SRR8381991.fastq.gz | Fastqsanger.gz | |||
| SRR8381982.fastq.gz | Fastqsanger.gz | |||
| SRR8381992.fastq.gz | Fastqsanger.gz | |||
| SRR8381983.fastq.gz | Fastqsanger.gz |
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Project description:Wnt/beta-catenin signaling is active in small subpopulations of Ewing sarcoma cells and these cells display a more metastatic phenotype, in part due to antagonism of EWS-FLI1-dependent transcriptional activity. Importantly, these beta-catenin-activated Ewing cells also alter secretion of extracellular matrix (ECM) proteins. We thus hypothesized that, in addition to cell autonomous mechanisms, Wnt/beta-catenin-active tumor cells might contribute to disease progression by altering the tumor microenvironment (TME). Activation of canonical Wnt signaling leads Ewing sarcoma cells to upregulate expression and secretion of pro-angiogenic ECM proteins, collectively termed the angiomatrix. Here we tested the role of Wnt-related TGF-beta signaling in angiomatrix induction by obtaining mRNA from Wnt3a-treated TC32 cells in the presence and absence of SB505124, a chemical inhibitor of TGF-beta receptor 1 (TGFBR1) and subjecting it to short read RNA-sequencing.
2020-06-23 | GSE124523 | GEO
Project description:Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta- catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells upregulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression.
2018-02-07 | PXD007909 | Pride
Project description:Ewing sarcomas are characterized by the presence of EWS/ETS fusion genes in the absence of other recurrent genetic alterations and mechanisms of tumor heterogeneity that contribute to disease progression remain unclear. Mutations in the Wnt/beta-catenin pathway are rare in Ewing sarcoma but the Wnt pathway modulator LGR5 is often highly expressed, suggesting a potential role for the axis in tumor pathogenesis. We evaluated beta-catenin and LGR5 expression in Ewing sarcoma cell lines and tumors and noted marked intra- and inter-tumor heterogeneity. Tumors with evidence of active Wnt/beta-catenin signaling were associated with increased incidence of tumor relapse and worse overall survival. Paradoxically, RNA sequencing revealed a marked antagonism of EWS/ETS transcriptional activity in Wnt/beta-catenin activated tumor cells. Consistent with this, Wnt/beta-catenin activated cells displayed a phenotype that was reminiscent of Ewing sarcoma cells with partial EWS/ETS loss of function. Specifically, activation of Wnt/beta-catenin induced alterations to the actin cytoskeleton, acquisition of a migratory phenotype and up regulation of EWS/ETS-repressed genes. Notably, activation of Wnt/beta-catenin signaling led to marked induction of tenascin C (TNC), an established promoter of cancer metastasis, and an EWS/ETS-repressed target gene. Loss of TNC function in Ewing sarcoma cells profoundly inhibited their migratory and metastatic potential. Our studies reveal that heterogeneous activation of Wnt/beta-catenin signaling in subpopulations of tumor cells contributes to phenotypic heterogeneity and disease progression in Ewing sarcoma. Significantly, this is mediated, at least in part, by inhibition of EWS/ETS fusion protein function that results in de-repression of metastasis-associated gene programs.
2016-11-30 | GSE75859 | GEO
Project description:Wnt/?-catenin signaling is active in small subpopulations of Ewing sarcoma cells, and these cells display a more metastatic phenotype, in part due to antagonism of EWS-FLI1-dependent transcriptional activity. Importantly, these ?-catenin-activated Ewing sarcoma cells also alter secretion of extracellular matrix (ECM) proteins. We thus hypothesized that, in addition to cell-autonomous mechanisms, Wnt/?-catenin-active tumor cells might contribute to disease progression by altering the tumor microenvironment (TME). Analysis of transcriptomic data from primary patient biopsies and from ?-catenin-active versus -nonactive tumor cells identified angiogenic switch genes as being highly and reproducibly upregulated in the context of ?-catenin activation. In addition, in silico and in vitro analyses, along with chorioallantoic membrane assays, demonstrated that ?-catenin-activated Ewing cells secreted factors that promote angiogenesis. In particular, activation of canonical Wnt signaling leads Ewing sarcoma cells to upregulate expression and secretion of proangiogenic ECM proteins, collectively termed the angiomatrix. Significantly, our data show that induction of the angiomatrix by Wnt-responsive tumor cells is indirect and is mediated by TGF-?. Mechanistically, Wnt/?-catenin signaling antagonizes EWS-FLI1-dependent repression of TGF-? receptor type 2, thereby sensitizing tumor cells to TGF-? ligands. Together, these findings suggest that Wnt/?-catenin-active tumor cells can contribute to Ewing sarcoma progression by promoting angiogenesis in the local TME.
| S-EPMC7406270 | biostudies-literature
Project description:This SuperSeries is composed of the following subset Series: GSE36857: Goldengate Methylation analysis: Ewing Sarcoma GSE36858: 5- AZA treatment of EWS cell lines Refer to individual Series
2012-09-01 | E-GEOD-36859 | biostudies-arrayexpress
Project description:Ewing sarcoma is an aggressive pediatric small round cell tumor that predominantly occurs in bone. Approximately 85% of Ewing sarcomas harbor the EWS/FLI fusion protein, which arises from a chromosomal translocation, t(11:22)(q24:q12). EWS/FLI interacts with numerous lineage-essential transcription factors to maintain mesenchymal progenitors in an undifferentiated state. We previously showed that EWS/FLI binds the osteogenic transcription factor RUNX2 and prevents osteoblast differentiation. In this study, we investigated the role of another Runt-domain protein, RUNX3, in Ewing sarcoma. RUNX3 participates in mesenchymal-derived bone formation and is a context dependent tumor suppressor and oncogene. RUNX3 was detected in all Ewing sarcoma cells examined, whereas RUNX2 was detected in only 73% of specimens. Like RUNX2, RUNX3 binds to EWS/FLI via its Runt domain. EWS/FLI prevented RUNX3 from activating the transcription of a RUNX-responsive reporter, p6OSE2. Stable suppression of RUNX3 expression in the Ewing sarcoma cell line A673 delayed colony growth in anchorage independent soft agar assays and reversed expression of EWS/FLI-responsive genes. These results demonstrate an important role for RUNX3 in Ewing sarcoma. RNA-seq to compare transcriptiome of control A673 ewing sarcoma cells stably expression a non-target or RUNX3 shRNA
2014-05-01 | E-GEOD-56900 | biostudies-arrayexpress
Project description:The expression profile of primary pediatric Ewing sarcoma (ES) and osteosarcoma (OS) were analyzed. 8 Ewing sarcoma patient samples (TUM-ES0XXX) and 10 osteosarcoma patient samples (TUM-OS0XXX) were analyzed.
2016-07-05 | E-GEOD-73166 | biostudies-arrayexpress
Project description:Study of promoter methylation of ewing sarcoma cell lines and mesenchymal stem cell from ewing sarcoma patients and healthy donors
2018-10-24 | GSE118872 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE17618: Inflammatory gene profiling of Ewing sarcoma family of tumors (set A) GSE17674: Inflammatory gene profiling of Ewing sarcoma family of tumors (set B) Refer to individual Series
2011-12-01 | E-GEOD-17679 | biostudies-arrayexpress