Oncogenic Phosphoinositide 3-Kinase signalling in Venous Malformations

Abstract

[eng] Venous malformations (VM), the most frequent type of vascular malformations, are localized developmental defects occurring during vascular morphogenesis that generat dilated, tortuous venous channels surrounded by erratically distributed mural cells and a disorganized extracellular matrix. VM often manifest sporadically at birth and grow over the time. They can be of different sizes and be present in any tissue resulting in chronic pathologies that are painful and lead to recurrent bleeding, infection and organ dysfunction. Current standard treatments are not fully efficient and are associated with high risk of recurrence and progression, claiming for an urgent need for targeted therapies.

From a biological perspective VM are considered as congenital errors affecting endothelial cells (ECs) or early endothelial progenitors, characterized by a constitutive activation of PI3K signalling pathway. Key discovering studies identified mutually exclusive somatic gain-of-function mutations in the endothelial PIK3CA gene or in the upstream endothelial tyrosine-kinase receptor TEK, as the genetic causes generating VM lesions.

However, the molecular and cellular mechanisms driven by PI3K signalling activation in ECs underlying the pathogenesis of VM remain unknown.

Here, by using an innovative approach that combines untargeted transcriptomics with unique in vitro and in vivo models, we investigated the pathogenic mechanisms induced by the expression of the oncogenic PIK3CA-H1047R activating mutation in ECs.

We confirm that ECs hyperproliferation is the triggering mechanism leading to abnormal dilated hyperplastic vascular channels in vivo. In addition, we discover that expression of the mutation induces a unique shift in the adhesive molecular signature of ECs, with a specific impact on the integrins profile, which can be rescued by the use of PI3K pathway inhibitors. Also, Pik3caH1047R expression leads to an increased capacity of ECs to migrate.

We postulate that altogether, the combination of an altered proliferative and migratory ECs behaviour causes defects in angiogenesis, showing a novel scenario for the pathogenesis of PI3K-driven VM. We identified the integrin-a9 as the most up-regulated integrin upon Pik3caH1047R expression in ECs and we propose that its role is key in mediating the aberrant ECs behaviour underlying the pathogenesis of VM.

Finally, we developed in vivo and in vitro pre-clinical models, which can be used in combination, to study the biology of VM, enabling the investigation and development of new personalized therapies on a patient-to-patient basis.