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VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis

ABSTRACT: Clinical sequencing efforts are rapidly identifying sarcoma gene fusions that lack functional validation. An example is the new fusion of transcriptional coactivators, VGLL2-NCOA2, found in infantile rhabdomyosarcoma. To delineate VGLL2-NCOA2 tumorigenic mechanisms and identify therapeutic vulnerabilities, we implemented a cross-species comparative oncology approach with zebrafish, mouse allograft, and patient samples. We found that VGLL2-NCOA2 is sufficient to generate mesenchymal tumors that display features of immature skeletal muscle and recapitulate the human disease. A subset of VGLL2-NCOA2 zebrafish tumors transcriptionally cluster with embryonic somitogenesis and identify VGLL2-NCOA2 developmental targets, including a RAS family GTPase, arf6/ARF6. In VGLL2-NCOA2 zebrafish, mouse allograft, and patient tumors, arf6/ARF6 is highly expressed and is absent from mature skeletal muscle. Moreover, ARF6 is overexpressed in adult and pediatric sarcoma subtypes. Our data indicate that VGLL2-NCOA2 is an oncogene which leverages developmental programs for tumorigenesis, and that the reactivation or persistence of arf6/ARF6 could represent a therapeutic opportunity.

ORGANISM(S): Mus musculus Danio rerio

PROVIDER: GSE206039 | GEO | 2023/01/16

REPOSITORIES: GEO

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VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis

Project description:VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis

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