PUBLICATION
VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis
- Authors
- Watson, S., LaVigne, C.A., Xu, L., Surdez, D., Cyrta, J., Calderon, D., Cannon, M.V., Kent, M.R., Silvius, K.M., Kucinski, J.P., Harrison, E.N., Murchison, W., Rakheja, D., Tirode, F., Delattre, O., Amatruda, J.F., Kendall, G.C.
- ID
- ZDB-PUB-230120-5
- Date
- 2023
- Source
- Cell Reports 42: 112013112013 (Journal)
- Registered Authors
- Amatruda, James F., Kendall, Genevieve, Murchison, Whitney
- Keywords
- CP: Cancer, cross-species comparative oncology, developmental biology, functional genomics, fusion oncogene, pediatric cancer, rhabdomyosarcoma
- Datasets
- GEO:GSE206039
- MeSH Terms
-
- Adult
- Animals
- Child
- Gene Fusion
- Humans
- Mice
- Muscle Proteins/genetics
- Nuclear Receptor Coactivator 2/genetics
- Rhabdomyosarcoma*/genetics
- Rhabdomyosarcoma*/pathology
- Sarcoma*
- Transcription Factors/genetics
- Zebrafish/metabolism
- PubMed
- 36656711 Full text @ Cell Rep.
Citation
Watson, S., LaVigne, C.A., Xu, L., Surdez, D., Cyrta, J., Calderon, D., Cannon, M.V., Kent, M.R., Silvius, K.M., Kucinski, J.P., Harrison, E.N., Murchison, W., Rakheja, D., Tirode, F., Delattre, O., Amatruda, J.F., Kendall, G.C. (2023) VGLL2-NCOA2 leverages developmental programs for pediatric sarcomagenesis. Cell Reports. 42:112013112013.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping