A zebrafish transgenic model of Ewing's sarcoma reveals conserved mediators of EWS-FLI1 tumorigenesis
- Authors
- Leacock, S.W., Basse, A.N., Chandler, G.L., Kirk, A.M., Rakheja, D., and Amatruda, J.F.
- ID
- ZDB-PUB-111025-2
- Date
- 2012
- Source
- Disease models & mechanisms 5(1): 95-106 (Journal)
- Registered Authors
- Amatruda, James F., Basse, Audrey, Kirk, Anne, Leacock, Stefanie
- Keywords
- none
- Datasets
- GEO:GSE31186, GEO:GSE31217, GEO:GSE31185
- MeSH Terms
-
- RNA-Binding Protein EWS/genetics
- RNA-Binding Protein EWS/metabolism*
- Proto-Oncogene Protein c-fli-1/genetics
- Proto-Oncogene Protein c-fli-1/metabolism*
- Gene Expression Regulation, Neoplastic
- Sarcoma, Ewing/genetics
- Sarcoma, Ewing/pathology*
- Humans
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish/metabolism*
- Animals
- Transgenes/genetics
- Neoplasm Transplantation
- Disease Models, Animal
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism*
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/pathology*
- Animals, Genetically Modified
- Embryo, Nonmammalian/metabolism
- Embryo, Nonmammalian/pathology
- Embryonic Development/genetics
- Gene Expression Profiling
- PubMed
- 21979944 Full text @ Dis. Model. Mech.
Ewing’s sarcoma, a malignant bone tumor of children and young adults, is a member of the small-round-blue-cell tumor family. Ewing’s sarcoma family tumors (ESFTs), which include peripheral primitive neuroectodermal tumors (PNETs), are characterized by chromosomal translocations that generate fusions between the EWS gene and ETS-family transcription factors, most commonly FLI1. The EWS-FLI1 fusion oncoprotein represents an attractive therapeutic target for treatment of Ewing’s sarcoma. The cell of origin of ESFT and the molecular mechanisms by which EWS-FLI1 mediates tumorigenesis remain unknown, and few animal models of Ewing’s sarcoma exist. Here, we report the use of zebrafish as a vertebrate model of EWS-FLI1 function and tumorigenesis. Mosaic expression of the human EWS-FLI1 fusion protein in zebrafish caused the development of tumors with histology strongly resembling that of human Ewing’s sarcoma. The incidence of tumors increased in a p53 mutant background, suggesting that the p53 pathway suppresses EWS-FLI1-driven tumorigenesis. Gene expression profiling of the zebrafish tumors defined a set of genes that might be regulated by EWS-FLI1, including the zebrafish ortholog of a crucial EWS-FLI1 target gene in humans. Stable zebrafish transgenic lines expressing EWS-FLI1 under the control of the heat-shock promoter exhibit altered embryonic development and defective convergence and extension, suggesting that EWS-FLI1 interacts with conserved developmental pathways. These results indicate that functional targets of EWS-FLI1 that mediate tumorigenesis are conserved from zebrafish to human and provide a novel context in which to study the function of this fusion oncogene.