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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.

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