title: Macrophage Metabolism Controls Tumor Blood Vessel Morphogenesis and Metastasis.
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.
authors: Lab of Tumor Inflammation and Angiogenesis, VIB, 3000 Leuven, Belgium; Lab of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors: Mathias
authors: M
authors: Wenes
authors: Lab of Tumor Inflammation and Angiogenesis, VIB, 3000 Leuven, Belgium; Lab of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors: Min
authors: M
authors: Shang
authors: Lab of Tumor Inflammation and Angiogenesis, VIB, 3000 Leuven, Belgium; Lab of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors: Mario
authors: M
authors: Di Matteo
authors: Lab of Angiogenesis and Vascular Metabolism, VIB, 3000 Leuven, Belgium; Lab of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors: Jermaine
authors: J
authors: Goveia
authors: Lab of Tumor Inflammation and Angiogenesis, VIB, 3000 Leuven, Belgium; Lab of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors: Rosa
authors: R
authors: Martín-Pérez
authors: Lab of Tumor Inflammation and Angiogenesis, VIB, 3000 Leuven, Belgium; Lab of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors: Jens
authors: J
authors: Serneels
authors: Department of Digestive Oncology, University Hospitals Leuven and Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors: Hans
authors: H
authors: Prenen
authors: Metabolomics Expertise Center, VIB, 3000 Leuven, Belgium; Metabolomics Expertise Center, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors: Bart
authors: B
authors: Ghesquière
authors: Lab of Angiogenesis and Vascular Metabolism, VIB, 3000 Leuven, Belgium; Lab of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors: Peter
authors: P
authors: Carmeliet
authors: Lab of Tumor Inflammation and Angiogenesis, VIB, 3000 Leuven, Belgium; Lab of Tumor Inflammation and Angiogenesis, Department of Oncology, KU Leuven, 3000 Leuven, Belgium. Electronic address: massimiliano.mazzone@vib-kuleuven.be.
authors: Massimiliano
authors: M
authors: Mazzone
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000254:growth & development* / Q000378:metabolism; D015687:Cell Hypoxia; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D008264:Macrophages / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C469992:Ddit4 protein, mouse; D014157:Transcription Factors; D058570:TOR Serine-Threonine Kinases; D005947:Glucose
keywords: angiogenesis; cancer; metabolism; metastasis; tumor-associated macrophages