Activation of Epidermal Growth Factor Receptor Pathway in Slow-Flow Vascular Malformations

Sporadic venous malformations (VM) and angiomatosis of soft tissue (AST) are benign, congenital slow-flow vascular anomalies that have no available targeted therapies. Depending on the size and location of the lesion, symptoms vary from motility disturbances to pain and disfigurement. In this work, we analyzed tissue samples from 36 patients with VM or AST. Additionally, patient-derived endothelialCD31+ and intervascular stromalCD31-, vimentin+ cells were used. Majority of the samples had a somatic mutation in either TEK or PIK3CA gene. Activation of ErbB1/EGFR pathway and expression of a pro-angiogenic ligand, transforming growth factor A, was found in both VM and AST samples. Activation of EGFR pathway led to the secretion of a major angiogenic factor VEGF-A. Intriguingly, patient-derived intervascular stromal cells were able to induce angiogenesis of genotypically normal endothelial cells via paracrine signaling. Significant decrease in endothelial sprouting and VEGF-A production were observed after treatment with a pan-ErbB inhibitor afatinib. To conclude, our data demonstrate that intervascular stromal cells play a role in the pathogenesis of AST and VM by producing pro-angiogenic factors that activate EGFR. Activation of EGFR pathway was not associated with a genetic cause but is likely caused by hypoxia. EGFR targeted therapy of both intervascular stromal cells and endothelial cells could be beneficial for the treatment of a subpopulation of AST and VM lesions expressing EGFR ligands. Overall design: Strand specific RNA-Seq of Human saphenous vein endothelial cells, Human umbilical vein endothelial cells and Human CD31+ endothelial cells extracted from vascular malformation ***Please note that, due to EU GDPR (EU2016/679) on personal data protection and legislation,and directives pertinent to the management of human data, only processed data is available for GSM3754280-GSM3754284. ***