Blockade of VEGF-C signaling inhibits lymphatic malformations driven by oncogenic PIK3CA mutation

Ines Martinez-Corral,Laurence Boon,Dieter Saur,Kari Alitalo,Mariona Graupera,Milena Petkova,Sandra D Castillo,Taija Mäkinen,Henrik Ortsäter,Louis Libbrecht,Sofie Sjöberg,Miikka Vikkula,Yan Zhang,Pascal Brouillard

doi:10.1038/s41467-020-16496-y

Abstract

Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Cellular mechanisms underlying LM pathology are poorly understood. Here we show that the somatic PIK3CAH1047R mutation, resulting in constitutive activation of the p110α PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CAH1047R-driven LM, we demonstrate that both types of malformations arise due to lymphatic endothelial cell (LEC)-autonomous defects, with the developmental timing of p110α activation determining the LM subtype. In the postnatal vasculature, PIK3CAH1047R promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow progressively in a vascular endothelial growth factor C (VEGF-C)-dependent manner. Combined inhibition of VEGF-C and the PI3K downstream target mTOR using Rapamycin, but neither treatment alone, promotes regression of lesions. The best therapeutic outcome for LM is thus achieved by co-inhibition of the upstream VEGF-C/VEGFR3 and the downstream PI3K/mTOR pathways.

Highlights

Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts or lesions that infiltrate tissues
To address whether the two subtypes of LM require different PIK3CA mutations, potentially driving different cellular responses, or if the same mutation can underlie both microcystic and macrocystic LMs, we focused on patients with a somatic PIK3CAH1047R mutation
Using a mouse model of LM driven by an activating PIK3CA mutation, we here characterize molecular and cellular mechanisms of lymphatic lesion formation and therapy response

Summary

Introduction

Lymphatic malformations (LMs) are debilitating vascular anomalies presenting with large cysts (macrocystic) or lesions that infiltrate tissues (microcystic). Often congenital pathologies that can manifest in different types of blood and lymphatic vessels. These diseases commonly arise from abnormalities in the endothelial cells (ECs) of the affected vessel type(s) that lead to structural and functional vascular defects causing deformation, pain, morbidity, and organ dysfunction[1]. The most common VM/LM mutations affecting the helical domain (E542K, E545K) or the kinase domain (H1047R, H1047L) of p110α are identical to those previously found in cancer and other genetic syndromes characterized by tissue overgrowth[9] Both types of mutations result in basal activation of the PI3K pathway by enhancing dynamic events in the natural activation of p110α that lead to increased lipid binding[10]. Regression of lesions is observed only in a minority of patients[3], which calls for a need to develop new more effective therapies

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