VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Cell Reports Year : 2023

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 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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inserm-04320607 , version 1 (04-12-2023)

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Sarah Watson, Collette A Lavigne, Lin Xu, Didier Surdez, Joanna Cyrta, et al.. VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis. Cell Reports, 2023, 42 (1), pp.112013. ⟨10.1016/j.celrep.2023.112013⟩. ⟨inserm-04320607⟩
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