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

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 PIK3CA^H1047R mutation, resulting in constitutive activation of the p110α PI3K, underlies both macrocystic and microcystic LMs in human. Using a mouse model of PIK3CA^H1047R-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, PIK3CA^H1047R promotes LEC migration and lymphatic hypersprouting, leading to microcystic LMs that grow prog

SUBMITTER: Martinez-Corral I 

PROVIDER: S-EPMC7280302 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature