Dataset Information

Wnt/?-catenin-activated Ewing sarcoma cells promote the angiogenic switch.

ABSTRACT: 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.

SUBMITTER: Hawkins AG

PROVIDER: S-EPMC7406270 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Wnt/β-catenin-activated Ewing sarcoma cells promote the angiogenic switch.

Hawkins Allegra G AG Pedersen Elisabeth A EA Treichel Sydney S Temprine Kelsey K Sperring Colin C Read Jay A JA Magnuson Brian B Chugh Rashmi R Lawlor Elizabeth R ER

JCI insight 20200709 13

Wnt/β-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 β-catenin-activated Ewing sarcoma cells also alter secretion of extracellular matrix (ECM) proteins. We thus hypothesized that, in addition to cell-autonomous mechanisms, Wnt/β-catenin-active tumor cells might contribute to disease progression by altering the tumor microe ...[more]

PMID: 32544094

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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.

Dataset Information

Wnt/?-catenin-activated Ewing sarcoma cells promote the angiogenic switch.

Publications

Wnt/β-catenin-activated Ewing sarcoma cells promote the angiogenic switch.

Similar Datasets

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