Cell Reports (Jan 2023)

VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis

  • Sarah Watson,
  • Collette A. LaVigne,
  • Lin Xu,
  • Didier Surdez,
  • Joanna Cyrta,
  • Delia Calderon,
  • Matthew V. Cannon,
  • Matthew R. Kent,
  • Katherine M. Silvius,
  • Jack P. Kucinski,
  • Emma N. Harrison,
  • Whitney Murchison,
  • Dinesh Rakheja,
  • Franck Tirode,
  • Olivier Delattre,
  • James F. Amatruda,
  • Genevieve C. Kendall

Journal volume & issue
Vol. 42, no. 1
p. 112013

Abstract

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Summary: Clinical sequencing efforts are rapidly identifying sarcoma gene fusions that lack functional validation. An example is the fusion of transcriptional coactivators, VGLL2-NCOA2, found in infantile rhabdomyosarcoma. To delineate VGLL2-NCOA2 tumorigenic mechanisms and identify therapeutic vulnerabilities, we implement a cross-species comparative oncology approach with zebrafish, mouse allograft, and patient samples. We find 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 programs, including a RAS family GTPase, ARF6. In VGLL2-NCOA2 zebrafish, mouse, and patient tumors, ARF6 is highly expressed. ARF6 knockout suppresses VGLL2-NCOA2 oncogenic activity in cell culture, and, more broadly, ARF6 is overexpressed in adult and pediatric sarcomas. Our data indicate that VGLL2-NCOA2 is an oncogene that leverages developmental programs for tumorigenesis and that reactivation or persistence of ARF6 could represent a therapeutic opportunity.

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