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

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

Affiliations

Sarah Watson: Institut Curie Research Center, Paris Sciences et Lettres (PSL) Research University, INSERM U830, 75005 Paris, France; Institut Curie, Paris Sciences et Lettres (PSL) Research University, Medical Oncology Department, 75005 Paris, France
Collette A. LaVigne: Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA
Lin Xu: Quantitative Biomedical Research Center, Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX 75390, USA
Didier Surdez: Institut Curie Research Center, Paris Sciences et Lettres (PSL) Research University, INSERM U830, 75005 Paris, France; Balgrist University Hospital, Faculty of Medicine, University of Zürich (UZH), 8008 Zürich, Switzerland
Joanna Cyrta: Institut Curie, Paris Sciences et Lettres (PSL) Research University, Department of Pathology, 75005 Paris, France
Delia Calderon: Center for Childhood Cancer, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; Molecular, Cellular, and Developmental Biology Ph.D. Program, The Ohio State University, Columbus, OH 43210, USA
Matthew V. Cannon: Center for Childhood Cancer, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA
Matthew R. Kent: Center for Childhood Cancer, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA
Katherine M. Silvius: Center for Childhood Cancer, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA
Jack P. Kucinski: Center for Childhood Cancer, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; Molecular, Cellular, and Developmental Biology Ph.D. Program, The Ohio State University, Columbus, OH 43210, USA
Emma N. Harrison: Center for Childhood Cancer, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA
Whitney Murchison: Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USA
Dinesh Rakheja: Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA
Franck Tirode: University Lyon, Université Claude Bernard Lyon 1, Cancer Research Center of Lyon, INSERM 1052, CNRS 5286, Centre LéonBérard, 69008 Lyon, France
Olivier Delattre: Institut Curie Research Center, Paris Sciences et Lettres (PSL) Research University, INSERM U830, 75005 Paris, France; Institut Curie, SIREDO Pediatric Center, 75005 Paris, France; Institut Curie Hospital Group, Unité de Génétique Somatique, 75005 Paris, France
James F. Amatruda: Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA 90027, USA; Departments of Pediatrics and Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Corresponding author
Genevieve C. Kendall: Center for Childhood Cancer, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH 43205, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA; Corresponding author

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

Abstract

Read online

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.

CP: Cancer

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

About the journal

Abstract

Keywords