Introduction of Mutant GNAQ into Endothelial Cells Induces a Vascular Malformation Phenotype with Therapeutic Response to Imatinib

• Authors: Maiko Sasaki, Emory University; Yppnhee Jung, Emory University; Paula North, Children’s Hospital of Wisconsin; Justin Elsey, Emory University; Keith Choate, Yale University; Michael Andrew Toussaint, Emory University; Christina Huang, Emory University; Rakan Radi, Emory University; Adam J Perricone, Emory University; Victor Corces, Emory University; Jack Arbiser, Emory University
• Journal Title: CANCERS
• Volume: Volume 14, Number 2
• Publisher: MDPI | 2022-01-01
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3390/cancers14020413
• Subjects: Health Sciences, Pathology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Oncology; GNAQ; vascular malformation; endothelial cells; Sturge Weber; vasculogenesis; STURGE-WEBER SYNDROME; SOMATIC MUTATION; BETA

Abstract

GNAQ is mutated in vascular and melanocytic lesions, including vascular malformations and nevi. No in vivo model of GNAQ activation in endothelial cells has previously been described. We introduce mutant GNAQ into a murine endothelial cell line, MS1. The resultant transduced cells exhibit a novel phenotype in vivo, with extensive vasoformative endothelial cells forming aberrant lumens similar to those seen in vascular malformations. ATAC-seq analysis reveals activation of c-Kit in the novel vascular malformations. We demonstrate that c-Kit is expressed in authentic human Sturge–Weber vascular malformations, indicating a novel druggable target for Sturge–Weber syndrome. Since c-Kit is targeted by the FDA-approved drug imatinib, we tested the ability of imatinib on the phenotype of the vascular malformations in vivo. Imatinib treated vascular malformations are significantly smaller and have decreased supporting stromal cells surrounding the lumen. Imatinib may be useful in the treatment of human vascular malformations that express c-Kit, including Sturge–Weber syndrome.