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

Maiko Sasaki,Rakan Radi,Yoonhee Jung,Christina Huang,Keith Choate,Paula North,Victor G Corces,Jack L Arbiser,Adam J Perricone,Justin Elsey,Michael Andrew Toussaint

doi:10.3390/cancers14020413

Abstract

Simple SummaryMutations in GNAQ underlie vascular malformations, including Sturge-Weber disease. In order to develop novel therapies for lesions with mutant GNAQ, we introduced mutant GNAQ into MS1 endothelial cells. Mutant GNAQ conferred a novel phenotype of progressive vascular malformations in mice. Chromatin analysis revealed upregulation of C-Kit in the vascular endothelial cells, and we found C-Kit to be highly expressed in Sturge-Weber disease. Given that imatinib is an FDA approved multikinase inhibitor that blocks C-Kit, we evaluated it in our mouse model, and showed that imatinib had activity against these vascular malformations. Repurposing imatinib should be evaluated in clinical trials, including Sturge-Weber disease.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.

Highlights

Introduction of Mutant GNAQ into EndothelialCells Induces a Vascular Malformation Phenotype with Therapeutic Response to ImatinibMaiko Sasaki 1,2, Yoonhee Jung 3, Paula North 4, Justin Elsey 1, Keith Choate 5, Michael Andrew Toussaint 6, Christina Huang 1, Rakan Radi 1, Adam J
We find that malformations caused by expression of GNAQ Q209L show a gain of 1952 and loss of 4366 transposase hypersensitive sites (THSSs) with respect to samples from mice injected with MS1 cells, suggesting a dramatic alteration in the binding of transcription factors (Figure 2A)
To examine whether c-Kit is associated with Sturge–Weber syndrome, we examined its expression in human Sturge–Weber Syndrome (SWS) tissue

Summary

Introduction

Introduction of Mutant GNAQ into EndothelialCells Induces a Vascular Malformation Phenotype with Therapeutic Response to ImatinibMaiko Sasaki 1,2 , Yoonhee Jung 3 , Paula North 4 , Justin Elsey 1 , Keith Choate 5 , Michael Andrew Toussaint 6 , Christina Huang 1 , Rakan Radi 1 , Adam J. Cells Induces a Vascular Malformation Phenotype with Therapeutic Response to Imatinib. Sturge–Weber Syndrome (SWS) is a relatively common vascular malformation responsible for significant morbidity and mortality. These includes pain, seizures, glaucoma, facial deformity and mental retardation [1,2,3,4]. SWS is caused by mutations of the GNAQ driver oncogene expressed in endothelial cells [5]. There are no known mouse models of vascular malformations caused by GNAQ mutation. In order to create a murine model of SWS, we used lentiviral introduction of mutant GNAQ into the murine microvascular MS1 cell line [7].

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