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

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

Authors :
Jay Read
Kelsey Temprine
Elizabeth R. Lawlor
Rashmi Chugh
Sydney Treichel
Elisabeth A. Pedersen
Colin Sperring
Brian Magnuson
Allegra G. Hawkins
Source :
JCI Insight
Publication Year :
2020
Publisher :
American Society for Clinical Investigation, 2020.

Abstract

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 microenvironment (TME). Analysis of transcriptomic data from primary patient biopsies and from β-catenin-active versus -nonactive tumor cells identified angiogenic switch genes as being highly and reproducibly upregulated in the context of β-catenin activation. In addition, in silico and in vitro analyses, along with chorioallantoic membrane assays, demonstrated that β-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-β. Mechanistically, Wnt/β-catenin signaling antagonizes EWS-FLI1-dependent repression of TGF-β receptor type 2, thereby sensitizing tumor cells to TGF-β ligands. Together, these findings suggest that Wnt/β-catenin-active tumor cells can contribute to Ewing sarcoma progression by promoting angiogenesis in the local TME.

Details

Language :
English
Database :
OpenAIRE
Journal :
JCI Insight
Accession number :
edsair.doi.dedup.....18429c7da5ba378687363c1468785724