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.
Highlights
Rhabdomyosarcoma (RMS) presents as a solid tumor that displays characteristics of primitive skeletal muscle (Parham and Ellison, 2006)
By implementing our CMV injected mosaic zebrafish models, we found that HES3 overexpression in zebrafish allows for PAX3-FOXO1+ cells to either inappropriately persist or divide, resulting in an increased number of observable GFP-PAX3FOXO1 + pixels by 24 hr post-fertilization (Figure 4—figure supplement 1A–C)
We focused on the human cell line, Rh30, which is derived from a bone marrow metastasis of ARMS and contains the PAX3-FOXO1 fusion (Hinson et al, 2013)
Summary
Rhabdomyosarcoma (RMS) presents as a solid tumor that displays characteristics of primitive skeletal muscle (Parham and Ellison, 2006). Kendall et al show that genetically engineered zebrafish with human PAX3-FOXO1 develop rhabdomyosarcoma-like tumors. Experiments on these zebrafish showed that the protein turns on a gene called her. In zebrafish or mouse cells, human HES3 interferes with muscle-cell maturation and allows cells that acquire PAX3-FOXO1 to persist during development instead of dying It increases the cell growth and cancerous behavior in human tumor cells. Its role as a cooperating gene in PAX3/7-FOXO1 fusion-positive rhabdomyosarcoma has never been described Taken together, this model represents a novel strategy to identify new targets and biomarkers in the context of human disease and contributes to our understanding of RMS biology by defining the earliest tumor initiation events
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