A zebrafish transgenic model of Ewing's sarcoma reveals conserved mediators of EWS-FLI1 tumorigenesis

• Published in: Disease models & mechanisms 2012-01, Vol.5 (1), p.95-106
• Main Authors: Leacock, Stefanie W, Basse, Audrey N, Chandler, Garvin L, Kirk, Anne M, Rakheja, Dinesh, Amatruda, James F
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Cancer; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Disease Models, Animal; Embryo, Nonmammalian - metabolism; Embryo, Nonmammalian - pathology; Embryonic Development - genetics; Ewings sarcoma; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Histology; Humans; Leukemia; Melanoma; Mutation; Neoplasm Transplantation; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Proto-Oncogene Protein c-fli-1 - genetics; Proto-Oncogene Protein c-fli-1 - metabolism; RNA-Binding Protein EWS - genetics; RNA-Binding Protein EWS - metabolism; Sarcoma; Sarcoma, Ewing - genetics; Sarcoma, Ewing - pathology; Transcription factors; Transgenes - genetics; Tumorigenesis; Tumors; Zebrafish; Zebrafish - embryology; Zebrafish - genetics; Zebrafish - metabolism
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.007401

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.