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

Stefanie W. Leacock, Audrey N. Basse, Garvin L. Chandler, Anne M. Kirk, Dinesh Rakheja, James F Amatruda

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)95-106
Number of pages12
JournalDMM Disease Models and Mechanisms
Volume5
Issue number1
DOIs
StatePublished - Jan 2012

Fingerprint

Ewing's Sarcoma
Zebrafish
Carcinogenesis
Tumors
Neoplasms
Fusion reactions
Genes
Oncogene Fusion
Peripheral Primitive Neuroectodermal Tumors
EWS-FLI fusion protein
Genetic Translocation
Histology
Oncogene Proteins
Gene Expression Profiling
Gene expression
Embryonic Development
Vertebrates
Young Adult
Shock
Bone

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Neuroscience (miscellaneous)

Cite this

A zebrafish transgenic model of Ewing's sarcoma reveals conserved mediators of EWS-FLI1 tumorigenesis. / Leacock, Stefanie W.; Basse, Audrey N.; Chandler, Garvin L.; Kirk, Anne M.; Rakheja, Dinesh; Amatruda, James F.

In: DMM Disease Models and Mechanisms, Vol. 5, No. 1, 01.2012, p. 95-106.

Research output: Contribution to journalArticle

Leacock, Stefanie W. ; Basse, Audrey N. ; Chandler, Garvin L. ; Kirk, Anne M. ; Rakheja, Dinesh ; Amatruda, James F. / A zebrafish transgenic model of Ewing's sarcoma reveals conserved mediators of EWS-FLI1 tumorigenesis. In: DMM Disease Models and Mechanisms. 2012 ; Vol. 5, No. 1. pp. 95-106.
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