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

Genevieve C. Kendall, Sarah Watson, Lin Xu, Collette A. Lavigne, Whitney Murchison, Dinesh Rakheja, Stephen X Skapek, Franck Tirode, Olivier Delattre, James F Amatruda

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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.

Original languageEnglish (US)
Article numbere33800
JournaleLife
Volume7
DOIs
StatePublished - Jun 5 2018

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Rhabdomyosarcoma
Zebrafish
Muscle Development
Carcinogenesis
Fusion reactions
Tumors
Muscle
Oncogene Fusion
Alveolar Rhabdomyosarcoma
Primitive Neuroectodermal Tumors
Pediatrics
Cell Lineage
Sarcoma
Neoplasms
Skeletal Muscle
Cells
Tissue
Survival

ASJC Scopus subject areas

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

Cite this

PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis. / Kendall, Genevieve C.; Watson, Sarah; Xu, Lin; Lavigne, Collette A.; Murchison, Whitney; Rakheja, Dinesh; Skapek, Stephen X; Tirode, Franck; Delattre, Olivier; Amatruda, James F.

In: eLife, Vol. 7, e33800, 05.06.2018.

Research output: Contribution to journalArticle

Kendall, Genevieve C. ; Watson, Sarah ; Xu, Lin ; Lavigne, Collette A. ; Murchison, Whitney ; Rakheja, Dinesh ; Skapek, Stephen X ; Tirode, Franck ; Delattre, Olivier ; Amatruda, James F. / PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis. In: eLife. 2018 ; Vol. 7.
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AU - Watson, Sarah

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AU - Murchison, Whitney

AU - Rakheja, Dinesh

AU - Skapek, Stephen X

AU - Tirode, Franck

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