Cellular and animal models of CLOVES syndrome

CLOVES (congenital lipomatous asymmetric overgrowth of the trunk with lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, and skeletal anomalies) is a recently described disorder belonging to nonhereditary syndromes and characterized by overgrowth of vascular and fibro-adipose tissues. Some 90 children worldwide have been diagnosed with CLOVES since 2006, when the condition was first characterized by the investigators. Presently there is no cure for CLOVES, only surgical treatments aimed at alleviating symptoms or managing the syndrome's progression. The discovery that activating mutations of PIK3CA are driving mutations in CLOVES syndrome opens new perspectives in managing the progression of this disease. However, to understand how PIK3CA mutations cause malformation and overgrowth it is necessary to develop cellular and animal models. The overall aim of this project is to produce biological models that phenocopy the alteration caused by activating mutation of PIK3CA gene. These models will help to understand the etiology of CLOVES and similar syndromes and to identify cell types that initiate the disease. Given that endothelial cells can acquire properties of mesenchymal stem-like cells, and further differentiate into osteoblasts, chondrocytes or adipocytes, we propose endothelial cells as disease-initiating cell in which targeting PIK3CA. We plan an experimental approach spanning from simple cellular models to ex-vivo and animal model of the diseases. In future, these models will enable to evaluate the efficacy of existing drugs, developed for cancer treatment, to cure CLOVES syndrome and related diseases.