Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function.

ABSTRACT: Complex lymphatic anomalies (CLAs) are sporadically occurring diseases caused by the maldevelopment of lymphatic vessels. We and others recently reported that somatic activating mutations in KRAS can cause CLAs. However, the mechanisms by which activating KRAS mutations cause CLAs are poorly understood. Here, we show that KRAS^G12D expression in lymphatic endothelial cells (LECs) during embryonic development impairs the formation of lymphovenous valves and causes the enlargement of lymphatic vessels. We demonstrate that KRAS^G12D expression in primary human LECs induces cell spindling, proliferation, and migration. It also increases AKT and ERK1/2 phosphorylation and decreases the expression of genes that regulate the maturation of lymphatic vessels. We sh

SUBMITTER: Fernandes LM 

PROVIDER: S-EPMC10571159 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature