Dysregulated heparan sulfate proteoglycan metabolism promotes Ewing sarcoma tumor growth
- Children's Hospital of Los Angeles, United States
Abstract
The Ewing sarcoma family of tumors is a group of malignant small round blue cell tumors (SRBCTs) that affects children, adolescents, and young adults. The tumors are characterized by reciprocal chromosomal translocations that generate chimeric fusion oncogenes, the most common of which is EWSR1-FLI1. Survival is extremely poor for patients with metastatic or relapsed disease, and no molecularly-targeted therapy for this disease currently exists. The absence of a reliable genetic animal model of Ewing sarcoma has impaired investigation of tumor cell/microenvironmental interactions in vivo. We have developed a new genetic model of Ewing sarcoma based on Cre-inducible expression of human EWSR1-FLI1 in wild type zebrafish, which causes rapid onset of SRBCTs at high penetrance. The tumors express canonical EWSR1-FLI1 target genes and stain for known Ewing sarcoma markers including CD99. Growth of tumors is associated with activation of the MAPK/ERK pathway, which we link to dysregulated extracellular matrix metabolism in general and heparan sulfate catabolism in particular. Targeting heparan sulfate proteoglycans with the specific heparan sulfate antagonist Surfen reduces ERK1/2 signaling and decreases tumorigenicity of Ewing sarcoma cells in vitro and in vivo. These results highlight the important role of the extracellular matrix in Ewing sarcoma tumor growth and the potential of agents targeting proteoglycan metabolism as novel therapies for this disease.
Data availability
Proteomics data have been deposited in Dryad (doi:10.5061/dryad.x95x69pj8)
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Proteomics analysis of normal and EWSR1-FLI1-expressing embryos/tissueDryad Digital Repository, doi:10.5061/dryad.x95x69pj8.
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Proteomics analysis of normal and EWSR1-FLI1-expressing embryos/tissueDryad Digital Repository, doi:10.5061/dryad.x95x69pj8.
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Inflammatory gene profiling of Ewing sarcoma family of tumors (set B)NCBI Gene Expression Omnibus, GSE17674.
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Gene Expression in Human RhabdomyosarcomaNCBI Gene Expression Omnibus, GSE108022.
Article and author information
Author details
Funding
National Cancer Institute (U54CA231649-01)
- James F Amatruda
1 Million 4 Anna
- James F Amatruda
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the University of Southern California, protocol number 21150.
Copyright
© 2022, Vasileva et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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