Dysregulated heparan sulfate proteoglycan metabolism promotes Ewing sarcoma tumor growth

Abstract
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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)

The following data sets were generated

1. Vasileva E
2. Amatruda JF
(2021) Proteomics analysis of normal and EWSR1-FLI1-expressing embryos/tissue
Dryad Digital Repository, doi:10.5061/dryad.x95x69pj8.

http://dx.doi.org/10.5061/dryad.x95x69pj8
(2021) Proteomics analysis of normal and EWSR1-FLI1-expressing embryos/tissue
Dryad Digital Repository, doi:10.5061/dryad.x95x69pj8.

https://doi.org/10.5061/dryad.x95x69pj8

The following previously published data sets were used

1. Savola S
2. Klami A
3. Myllykangas S
4. Manara C
5. Scotlandi K
6. Picci P
7. Knuutila S
8. Vakkila J
(2009) Inflammatory gene profiling of Ewing sarcoma family of tumors (set B)
NCBI Gene Expression Omnibus, GSE17674.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE17674
(2017) Gene Expression in Human Rhabdomyosarcoma
NCBI Gene Expression Omnibus, GSE108022.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE108022

Article and author information

Author details

Elena Vasileva

Cancer and Blood Disease Institute, Children's Hospital of Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Mikako Warren

Division of Pathology and Laboratory Medicine, Children's Hospital of Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
Timothy J Triche

Division of Pathology and Laboratory Medicine, Children's Hospital of Los Angeles, Los Angeles, United States

Competing interests
The authors declare that no competing interests exist.
James F Amatruda

Department of Pediatrics, Children's Hospital of Los Angeles, Los Angeles, United States

For correspondence
jamatruda@chla.usc.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9901-2137

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

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.