title: Fatty acid synthase is a metabolic oncogene targetable in malignant peripheral nerve sheath tumors.
abstract: BACKGROUND
  Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas with minimal therapeutic opportunities. We observed that lipid droplets (LDs) accumulate in human MPNST cell lines and in primary human tumor samples. The goal of this study was to investigate the relevance of lipid metabolism to MPNST survival and as a possible therapeutic target.
  
  
  METHODS
  Based on preliminary findings that MPNSTs accumulate LDs, we hypothesized that a deregulated lipid metabolism supports MPNST cell survival/proliferation rate. To test this, we examined respiration, role of fatty acid oxidation (FAO), and the enzyme fatty acid synthase involved in de novo fatty acid synthesis in MPNSTs using both genetic and pharmacological tools.
  
  
  RESULTS
  We demonstrate that LDs accumulate in MPNST cell lines, primary human and mouse MPNST tumors, and neural crest cells. LDs from MPNST cells disappear on lipid deprivation, indicating that LDs can be oxidized as a source of energy. Inhibition of FAO decreased oxygen consumption and reduced MPNST survival, indicating that MPNST cells likely metabolize LDs through active FAO. FAO inhibition reduced oxygen consumption and survival even in the absence of exogenous lipids, indicating that lipids synthesized de novo can also be oxidized. Consequently, inhibition of de novo fatty acid synthesis, which is overexpressed in human MPNST cell lines, effectively reduced MPNST survival and delayed induction of tumor growth in vivo.
  
  
  CONCLUSIONS
  Our results show that MPNSTs depend on lipid metabolic pathways and suggest that disrupting lipid metabolism could be a potential new strategy for the development of MPNST therapeutics.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA (A.V.P., N.R.); Division of Oncology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA (B.D.); Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden (G.J.); Assistant Director for Compliance, Office of Intramural Research, National Institute of Health (M.C.C.).
authors.forename: Ami V
authors.initials: AV
authors.lastname: Patel
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA (A.V.P., N.R.); Division of Oncology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA (B.D.); Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden (G.J.); Assistant Director for Compliance, Office of Intramural Research, National Institute of Health (M.C.C.).
authors.forename: Gunnar
authors.initials: G
authors.lastname: Johansson
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA (A.V.P., N.R.); Division of Oncology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA (B.D.); Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden (G.J.); Assistant Director for Compliance, Office of Intramural Research, National Institute of Health (M.C.C.).
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Colbert
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA (A.V.P., N.R.); Division of Oncology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA (B.D.); Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden (G.J.); Assistant Director for Compliance, Office of Intramural Research, National Institute of Health (M.C.C.).
authors.forename: Biplab
authors.initials: B
authors.lastname: Dasgupta
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA (A.V.P., N.R.); Division of Oncology, Cincinnati Children's Hospital, Cincinnati, Ohio, USA (B.D.); Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden (G.J.); Assistant Director for Compliance, Office of Intramural Research, National Institute of Health (M.C.C.).
authors.forename: Nancy
authors.initials: N
authors.lastname: Ratner
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D066292:Lipid Droplets / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009432:Neural Crest / Q000378:metabolism; D009442:Neurilemmoma / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D064429:Fatty Acid Synthases; D015107:4-Butyrolactone
keywords: C75; FASN; MPNST; lipid droplet; sarcoma