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

Alveolar rhabdomyosarcoma is a pediatric soft-tissue sarcoma caused byPAX3/7-FOXO1 fusion oncogenes and is characterized by impaired skeletal muscle development. We developed humanPAX3-FOXO1 -driven zebrafish models of tumorigenesis and found thatPAX3-FOXO1 exhibits discrete cell lineage susceptibility and transformation. Tumors developed by 1.6 –19 months and were primitive neuroectodermal tumors or rhabdomyosarcoma. We applied thisPAX3-FOXO1 transgenic zebrafish model to study howPAX3-FOXO1 leverages early developmental pathways for oncogenesis and found thather3 is a unique target. Ectopic expression of theher3 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 newPAX3-FOXO1 target,her3/HES3, that contributes to impaired myogenic differentiation and has prognostic significance in human disease.
Source: eLife - Category: Biomedical Science Tags: Cancer Biology Developmental Biology and Stem Cells Source Type: research