Boscolo Lab Research Projects

Venous Malformation

Venous Malformations (VM) is a developmental chronic vascular anomaly characterized by massively dilated (ectatic) veins with hyperactive somatic mutations of the TIE2 kinase receptor or PIK3CA.

We have developed state-of-art tools to study VM and investigate the cellular and molecular mechanisms leading to VM formation and maintenance.

1. In 2015 we generated a revolutionary patient mutation-based xenograft model of VM. This model was instrumental to establish the efficacy of the mTOR inhibitor rapamycin in preventing expansion of the lesions in mouse. The success of our discovery culminated into efficacious and safe targeted treatment with Sirolimus (rapamycin) in patients affected by VM.
2. In 2019 we devised a three-dimensional (3D) system to recapitulate the ectatic lumen formation which characterizes VM endothelial cells in patient’s affected tissue.
3. Currently we are generating a transgenic murine model expressing the most common TIE2 mutation p.L914F in endothelial cells.

With a combination of these 3 tools and the use of patient tissue and cells, we are investigating the following research questions:

• Identify signaling molecules driving aberrant enlargement of vascular lumens (c-Abl, Rac1 and Semaphorins).
• Establish cell-cell communication mechanisms of mutant cells with normal endothelial cells.
• Identify efficacious targeted therapies that can be used alone or in combination with rapamycin.

GNAQ-related Vascular Anomalies

A class of disfiguring and life-threatening vascular tumors are associated with the p.Q209L mutation in the guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) gene family causing excessive, uncontrolled activity of the protein encoded by this gene. A roadblock to finding effective, non-invasive treatments has been the lack of animal models for the study of disease development and targeted treatment. We have developed a murine model of GNAQ mutant vascular tumors that recapitulate the patients’ disease progression and complications. In preclinical studies with this model, we showed hyperactivation of the MAPK signaling pathway and that targeted treatment with the MAPK inhibitor Trametinib can improve survival by reducing cell proliferation and preventing the development of the coagulopathy complication.

Current work in the Boscolo Lab is investigating:

• The molecular consequences of gain-of-function GNAQ mutations in the vasculature.
• We are performing preclinical studies in our murine model to develop effective targeted therapies.
• We are investigating the cellular and molecular mechanisms driving the life-threatening coagulopathy which is a severe complication in affected patients.

Capillary Lymphatic Venous Malformation

Capillary lymphatic venous malformations (CLVM) are complex vascular anomalies that appear during fetal development and cause life-long complications such as coagulopathy, pulmonary embolism, chronic pain, and severe disfigurement. Non-inherited, (somatic) mosaic mutations in the 110-kD catalytic α-subunit of phosphoinositide-3-kinase (PIK3CA) gene have been identified in affected tissues from CLVM patients.

In collaboration with the laboratory of Dr. Timothy Le Cras we are currently testing the hypothesis that PIK3CA mutations originate in the EC population of CLVM lesions. To test our hypothesis, we devised a protocol to isolate and purify EC from human CLVM lesion tissue. To study the EC contribution to disease, we are generating a xenograft model by injecting patient-derived EC into mice.  Our future studies will focus on the identification of novel molecular targeted therapies, biomarkers and crosstalk between EC and stromal cells.