PUBLICATION

PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis.

Authors
Kendall, G.C., Watson, S., Xu, L., LaVigne, C.A., Murchison, W., Rakheja, D., Skapek, S.X., Tirode, F., Delattre, O., Amatruda, J.F.
ID
ZDB-PUB-180606-10
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
  • Mice
  • Zebrafish/metabolism
  • Zebrafish/physiology*
  • DNA-Binding Proteins/genetics
  • DNA-Binding Proteins/metabolism*
  • Gene Expression Regulation, Neoplastic
  • Embryo, Nonmammalian/cytology
  • Embryo, Nonmammalian/metabolism
  • Cell Proliferation
  • PAX3 Transcription Factor/genetics
  • PAX3 Transcription Factor/metabolism
  • Transcription Factors/genetics
  • Transcription Factors/metabolism*
  • Humans
  • Myoblasts/metabolism
  • Myoblasts/pathology
  • Forkhead Box Protein O1/genetics
  • Forkhead Box Protein O1/metabolism
  • Rhabdomyosarcoma/genetics
  • Rhabdomyosarcoma/metabolism
  • Rhabdomyosarcoma/pathology*
  • Cell Differentiation
  • Animals
  • Cells, Cultured
  • Muscle Development
  • Carcinogenesis/genetics
  • Carcinogenesis/metabolism
  • Carcinogenesis/pathology*
(all 28)
PubMed
29869612 Full text @ Elife
Abstract
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.
Genes / Markers
Figures
Figure Gallery (5 images)
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
zdf1
    		Point Mutation
    1 - 1 of 1
    Show
    Human Disease / Model
    Human Disease Fish Conditions Evidence
    alveolar rhabdomyosarcomaTAS
    1 - 1 of 1
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    Sequence Targeting Reagents
    No data available
    Fish
    No data available
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    No data available
    Mapping
    No data available
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    Citation
    Kendall, G.C., Watson, S., Xu, L., LaVigne, C.A., Murchison, W., Rakheja, D., Skapek, S.X., Tirode, F., Delattre, O., Amatruda, J.F. (2018) PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis.. eLIFE. 7.