Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, Endocrinology & Metabolism, MAMMALIAN TARGET, MTOR PATHWAY, ANGIOGENESIS, POLARIZATION, RAPAMYCIN, HYPOXIA, GROWTH, CELLS, PIMONIDAZOLE, BINDING, angiogenesis, cancer, metabolism, metastasis, tumor-associated macrophages, Animals, Blood Vessels, Cell Hypoxia, Disease Models, Animal, Endothelial Cells, Gene Deletion, Glucose, Glycolysis, Macrophages, Mice, Inbred C57BL, Mice, Knockout, Morphogenesis, Neoplasm Metastasis, Neoplasms, Neovascularization, Pathologic, Signal Transduction, TOR Serine-Threonine Kinases, Transcription Factors, Up-Regulation, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 3101 Biochemistry and cell biology, 3205 Medical biochemistry and metabolomics

Abstract:

Hypoxic tumor-associated macrophages (TAMs) acquire angiogenic and immunosuppressive properties. Yet it remains unknown if metabolic changes influence these functions. Here, we argue that hypoxic TAMs strongly upregulate the expression of REDD1, a negative regulator of mTOR. REDD1-mediated mTOR inhibition hinders glycolysis in TAMs and curtails their excessive angiogenic response, with consequent formation of abnormal blood vessels. Accordingly, REDD1 deficiency in TAMs leads to the formation of smoothly aligned, pericyte-covered, functional vessels, which prevents vessel leakiness, hypoxia, and metastases. Mechanistically, highly glycolytic REDD1-deficient TAMs outcompete endothelial cells for glucose usage that thwarts vascular hyperactivation and promotes the formation of quiescent vascular junctions. Tuning down glycolysis in REDD1 knockout TAMs re-establishes abnormal angiogenesis and metastases. On this basis, we prove that the anti-tumor effect of mTOR inhibitors is partly countered by the deleterious outcome of these drugs on TAMs. Our data provide a functional link between TAM metabolism and tumor angiogenesis.