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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
- 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.
- Subjects :
- 0301 basic medicine
Angiogenic Switch
Oncogene Proteins, Fusion
Angiogenesis
Sarcoma, Ewing
Extracellular matrix
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
medicine
Tumor Microenvironment
Humans
Secretion
Wnt Signaling Pathway
Tumor microenvironment
Chemistry
Proto-Oncogene Protein c-fli-1
Wnt signaling pathway
General Medicine
medicine.disease
Up-Regulation
Gene Expression Regulation, Neoplastic
030104 developmental biology
030220 oncology & carcinogenesis
Catenin
Cancer research
Sarcoma
RNA-Binding Protein EWS
Research Article
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- JCI Insight
- Accession number :
- edsair.doi.dedup.....18429c7da5ba378687363c1468785724