PUBLICATION
Dysregulated heparan sulfate proteoglycan metabolism promotes Ewing sarcoma tumor growth
- Authors
- Vasileva, E., Warren, M., Triche, T.J., Amatruda, J.F.
- ID
- ZDB-PUB-220315-28
- Date
- 2022
- Source
- eLIFE 11: (Journal)
- Registered Authors
- Amatruda, James F., Vasileva, Elena
- Keywords
- cancer biology, zebrafish
- MeSH Terms
-
- Adolescent
- Zebrafish/metabolism
- Sarcoma, Ewing*/genetics
- Sarcoma, Ewing*/pathology
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism
- Humans
- Heparan Sulfate Proteoglycans/metabolism
- Animals
- RNA-Binding Protein EWS/genetics
- RNA-Binding Protein EWS/metabolism
- PubMed
- 35285802 Full text @ Elife
Citation
Vasileva, E., Warren, M., Triche, T.J., Amatruda, J.F. (2022) Dysregulated heparan sulfate proteoglycan metabolism promotes Ewing sarcoma tumor growth. eLIFE. 11:.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping