<i>PAX3-FOXO1</i> transgenic zebrafish models identify <i>HES3</i> as a mediator of rhabdomyosarcoma tumorigenesis.

Abstract

Alveolar rhabdomyosarcoma is a pediatric soft-tissue sarcoma caused by <i>PAX3/7-FOXO1</i> fusion oncogenes and is characterized by impaired skeletal muscle development. We developed human <i>PAX3-FOXO1</i> -driven zebrafish models of tumorigenesis and found that <i>PAX3-FOXO1</i> exhibits discrete cell lineage susceptibility and transformation. Tumors developed by 1.6-19 months and were primitive neuroectodermal tumors or rhabdomyosarcoma. We applied this <i>PAX3-FOXO1</i> transgenic zebrafish model to study how <i>PAX3-FOXO1</i> leverages early developmental pathways for oncogenesis and found that <i>her3</i> is a unique target. Ectopic expression of the <i>her3</i> human ortholog, <i>HES3</i>, inhibits myogenesis in zebrafish and mammalian cells, recapitulating the arrested muscle development characteristic of rhabdomyosarcoma. In patients, <i>HES3</i> is overexpressed in fusion-positive versus fusion-negative tumors. Finally, <i>HES3</i> overexpression is associated with reduced survival in patients in the context of the fusion. Our novel zebrafish rhabdomyosarcoma model identifies a new <i>PAX3-FOXO1</i> target, <i>her3</i>/<i>HES3</i>, that contributes to impaired myogenic differentiation and has prognostic significance in human disease.