Wnt/beta-catenin activated Ewing sarcoma cells promote the angiogenic switch
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PROVIDER: PRJNA512292 | ENA |
REPOSITORIES: ENA
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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: Not available
| S-EPMC7406270 | biostudies-literature
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:A group of colorectal cancer (CRC) patients treated with chemotherapy and Bevacizumab (Bev) maintain the same sensitivity after progression to maintenance treatment because they remain dependent on VEGF angiogenic mediator, while other patients in whom there is an angiogenic switch (AS) become dependent on other angiogenic cytokines and become resistant to Bev chemotherapy combinations .
| 2161751 | ecrin-mdr-crc
Project description: Not available
| S-EPMC3625903 | biostudies-other
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:The cellular origin of Ewing tumor (ET), a tumor of bone or soft tissues characterized by specific fusions between EWS and ETS genes, is highly debated. Through gene expression analysis comparing ETs with a variety of normal tissues, we show that the profiles of different EWS-FLI1-silenced Ewing cell lines converge toward that of mesenchymal stem cells (MSC). Moreover, upon EWS-FLI1 silencing, two different Ewing cell lines can differentiate along the adipogenic lineage when incubated in appropriate differentiation cocktails. In addition, Ewing cells can also differentiate along the osteogenic lineage upon long-term inhibition of EWS-FLI1. These in silico and experimental data strongly suggest that the inhibition of EWS-FLI1 may allow Ewing cells to recover the phenotype of their MSC progenitor. Experiment Overall Design: Ewing tumors and EWS-FLI-1 inhibited cell lines were profiled on Affymetrix U133A (GPL96) arrays.
2008-06-15 | E-GEOD-7007 | biostudies-arrayexpress
Project description:Angiogenesis represents a rate-limiting step during tumor progression. Molecular mechanisms driving tumor angiogenesis (e.g. implicating signaling by VEGFs and their receptors) have been elucidated and allowed to design targeted therapies. However, limits of such anti-angiogenic therapies have emerged, notably because tumor cells adapt and tumors recur in more aggressive fashions. There is therefore a need to identify novel mechanisms implicated in tumor angiogenesis that have a potential towards translational applications. Using a transgenic murine model of pancreatic neuroendocrine cancer (Hanahan, Nature 315, 1985) where angiogenesis represents an early and discrete step of multi-stage tumor progression (Folkman et al. , Nature 339, 1989), we compared non-angiogenic and angiogenic early tumors to obtain a comprehensive description of the tumor angiogenic switch at the level of gene expression.
2015-01-01 | GSE51637 | GEO
Project description:Naba A, Clauser KR, Mani DR, Carr SA, Hynes RO. The angiogenic switch, the time at which a tumor becomes vascularized, is a critical step in tumor progression. Indeed, it has been demonstrated that without blood supply, tumors will fail to grow beyond 1mm3 and are unlikely to disseminate. The extracellular matrix (ECM), a major component of the tumor microenvironment, is known to undergo significant changes during tumor progression and, in particular, during angiogenesis. However the extent of these changes remains unknown. In this study, we used quantitative proteomics to characterize the composition of the ECM of pancreatic islets in a transgenic mouse model of insulinoma characterized by a precisely timed angiogenic switch. Out of the 120 ECM proteins quantified, 35 were detected in significantly different abundance as pancreatic islets progressed from being hyperplastic to angiogenic to insulinomas. Among these, the core ECM proteins, EFEMP1, Fibrillin 1 and periostin were found in higher abundance, and decorin, Dmbt1, hemicentin and Vwa5 in lower abundance during tumor progression. The angiogenic switch being a common feature of solid tumors, we propose that some of the proteins identified represent potential novel anti-angiogenic targets. In addition, we report here the characterization of the ECM composition of normal pancreatic islets and propose that this could be of interest for the design of tissue engineering and regenerative strategies for treatment of diabetes.
| MSV000080124 | MassIVE