title: Blocking lipid synthesis overcomes tumor regrowth and metastasis after antiangiogenic therapy withdrawal.
abstract: The molecular mechanisms responsible for the failure of antiangiogenic therapies and how tumors adapt to these therapies are unclear. Here, we applied transcriptomic, proteomic, and metabolomic approaches to preclinical models and provide evidence for tumor adaptation to vascular endothelial growth factor blockade through a metabolic shift toward carbohydrate and lipid metabolism in tumors. During sunitinib or sorafenib treatment, tumor growth was inhibited and tumors were hypoxic and glycolytic. In sharp contrast, treatment withdrawal led to tumor regrowth, angiogenesis restoration, moderate lactate production, and enhanced lipid synthesis. This metabolic shift was associated with a drastic increase in metastatic dissemination. Interestingly, pharmacological lipogenesis inhibition with orlistat or fatty acid synthase downregulation with shRNA inhibited tumor regrowth and metastases after sunitinib treatment withdrawal. Our data shed light on metabolic alterations that result in cancer adaptation to antiangiogenic treatments and identify key molecules involved in lipid metabolism as putative therapeutic targets.
authors.affiliation: Laboratory of Tumor and Developmental Biology, GIGA-CANCER, University of Liege, 4000 Liege, Belgium. Electronic address: nesounni@ulg.ac.be.
authors.forename: Nor Eddine
authors.initials: NE
authors.lastname: Sounni
authors.affiliation: Laboratory of Tumor and Developmental Biology, GIGA-CANCER, University of Liege, 4000 Liege, Belgium; Mass Spectrometry Laboratory, GIGA-R, Department of Chemistry, University of Liege, 4000 Liege, Belgium.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cimino
authors.affiliation: Laboratory of Tumor and Developmental Biology, GIGA-CANCER, University of Liege, 4000 Liege, Belgium.
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.affiliation: Laboratory of Tumor and Developmental Biology, GIGA-CANCER, University of Liege, 4000 Liege, Belgium.
authors.forename: Irina
authors.initials: I
authors.lastname: Primac
authors.affiliation: Laboratory of Tumor and Developmental Biology, GIGA-CANCER, University of Liege, 4000 Liege, Belgium.
authors.forename: Alice
authors.initials: A
authors.lastname: Truong
authors.affiliation: Mass Spectrometry Laboratory, GIGA-R, Department of Chemistry, University of Liege, 4000 Liege, Belgium.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Mazzucchelli
authors.affiliation: Laboratory of Tumor and Developmental Biology, GIGA-CANCER, University of Liege, 4000 Liege, Belgium.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Paye
authors.affiliation: Mass Spectrometry Laboratory, GIGA-R, Department of Chemistry, University of Liege, 4000 Liege, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Calligaris
authors.affiliation: Mass Spectrometry Laboratory, GIGA-R, Department of Chemistry, University of Liege, 4000 Liege, Belgium.
authors.forename: Delphine
authors.initials: D
authors.lastname: Debois
authors.affiliation: Laboratory of Drug Research Center, University of Liege, 4000 Liege, Belgium.
authors.forename: Pascal
authors.initials: P
authors.lastname: De Tullio
authors.affiliation: UMR-7275 CNRS, University of Nice Sophia-Antipolis, Institute of Molecular and Cellular Pharmacology, 06560 Valbonne, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Mari
authors.affiliation: Mass Spectrometry Laboratory, GIGA-R, Department of Chemistry, University of Liege, 4000 Liege, Belgium.
authors.forename: Edwin
authors.initials: E
authors.lastname: De Pauw
authors.affiliation: Laboratory of Tumor and Developmental Biology, GIGA-CANCER, University of Liege, 4000 Liege, Belgium.
authors.forename: Agnes
authors.initials: A
authors.lastname: Noel
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D018450:Disease Progression; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008055:Lipids / Q000096:biosynthesis*; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D040901:Proteomics; D011758:Pyrroles / Q000627:therapeutic use; D034622:RNA Interference; D000077157:Sorafenib; D000077210:Sunitinib; D014183:Transplantation, Heterologous
chemical_list: D020533:Angiogenesis Inhibitors; D018398:Homeodomain Proteins; D007211:Indoles; D008055:Lipids; D010671:Phenylurea Compounds; D011758:Pyrroles; C064658:RAG-1 protein; D009536:Niacinamide; D000077157:Sorafenib; D064429:Fatty Acid Synthases; D000077210:Sunitinib