Macrophage metabolism controls blood vessel morphogenesis and metastasis

Abstract

Tumor-associated macrophages (TAMs) display different phenotypes and specific metabolic fingerprints. Yet, whether and how metabolism influences TAM functions remains unknown. We report that REDD1, a negative regulator of the energy/nutrient sensor mTOR, is greatly induced in hypoxic TAMs. mTOR inhibition by REDD1 sustains the angiogenic capacity of TAMs, contributing to the formation of aberrant blood vessels. Genetic deletion of REDD1 leads to the formation of smoothly aligned, pericyte-covered blood vessels, which prevents hypoxia and metastasis in several tumor models. Molecularly, REDD1 inactivation unleashes mTOR in hypoxic TAMs thus enhancing glycolysis and NADH production, hence feeding a burst of mitochondrial ROS. ROS signaling stabilizes NF-κB that drives an angiostatic TAM phenotype, partly through the augmented production of the peptidase-inhibitor bectenecin. Systemic mTOR inhibition also promotes vessel abnormalization and metastasis, mostly due to its effect on TAMs. Our data provide a mechanism whereby TAM metabolism in hypoxia governs vascular remodeling and metastasis.nrpages: 114status: publishe