ZFIN ID: ZDB-PUB-180606-10
PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis.
Kendall, G.C., Watson, S., Xu, L., LaVigne, C.A., Murchison, W., Rakheja, D., Skapek, S.X., Tirode, F., Delattre, O., Amatruda, J.F.
Date: 2018
Source: eLIFE   7: (Journal)
Registered Authors: Amatruda, James F., Kendall, Genevieve, Murchison, Whitney
Keywords: HES3, PAX3-FOXO1, cancer biology, developmental biology, fusion oncogene, human, mouse, muscle, rhabdomyosarcoma, sarcoma, stem cells, zebrafish
MeSH Terms:
  • Animals
  • Carcinogenesis/genetics
  • Carcinogenesis/metabolism
  • Carcinogenesis/pathology*
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • DNA-Binding Proteins/genetics
  • DNA-Binding Proteins/metabolism*
  • Embryo, Nonmammalian/cytology
  • Embryo, Nonmammalian/metabolism
  • Forkhead Box Protein O1/genetics
  • Forkhead Box Protein O1/metabolism
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice
  • Muscle Development
  • Myoblasts/metabolism
  • Myoblasts/pathology
  • PAX3 Transcription Factor/genetics
  • PAX3 Transcription Factor/metabolism
  • Rhabdomyosarcoma/genetics
  • Rhabdomyosarcoma/metabolism
  • Rhabdomyosarcoma/pathology*
  • Transcription Factors/genetics
  • Transcription Factors/metabolism*
  • Zebrafish/metabolism
  • Zebrafish/physiology*
PubMed: 29869612 Full text @ Elife
Alveolar rhabdomyosarcoma is a pediatric soft-tissue sarcoma caused by PAX3/7-FOXO1 fusion oncogenes and is characterized by impaired skeletal muscle development. We developed human PAX3-FOXO1 -driven zebrafish models of tumorigenesis and found that PAX3-FOXO1 exhibits discrete cell lineage susceptibility and transformation. Tumors developed by 1.6-19 months and were primitive neuroectodermal tumors or rhabdomyosarcoma. We applied this PAX3-FOXO1 transgenic zebrafish model to study how PAX3-FOXO1 leverages early developmental pathways for oncogenesis and found that her3 is a unique target. Ectopic expression of the her3 human ortholog, HES3, inhibits myogenesis in zebrafish and mammalian cells, recapitulating the arrested muscle development characteristic of rhabdomyosarcoma. In patients, HES3 is overexpressed in fusion-positive versus fusion-negative tumors. Finally, HES3 overexpression is associated with reduced survival in patients in the context of the fusion. Our novel zebrafish rhabdomyosarcoma model identifies a new PAX3-FOXO1 target, her3/HES3, that contributes to impaired myogenic differentiation and has prognostic significance in human disease.