title: Myc Expression Drives Aberrant Lipid Metabolism in Lung Cancer.
abstract: MYC-mediated pathogenesis in lung cancer continues to attract interest for new therapeutic strategies. In this study, we describe a transgenic mouse model of KRAS-driven lung adenocarcinoma that affords reversible activation of MYC, used here as a tool for lipidomic profiling of MYC-dependent lung tumors formed in this model. Advanced mass spectrometric imaging and surface analysis techniques were used to characterize the spatial and temporal changes in lipid composition in lung tissue. We found that normal lung tissue was characterized predominantly by saturated phosphatidylcholines and phosphatidylglycerols, which are major lipid components of pulmonary surfactant. In contrast, tumor tissues displayed an increase in phosphatidylinositols and arachidonate-containing phospholipids that can serve as signaling precursors. Deactivating MYC resulted in a rapid and dramatic decrease in arachidonic acid and its eicosanoid metabolites. In tumors with high levels of MYC, we found an increase in cytosolic phospholipase A2 (cPLA2) activity with a preferential release of membrane-bound arachidonic acid, stimulating the lipoxygenase (LOX) and COX pathways also amplified by MYC at the level of gene expression. Deactivating MYC lowered cPLA2 activity along with COX2 and 5-LOX mRNA levels. Notably, inhibiting the COX/5-LOX pathways in vivo reduced tumor burden in a manner associated with reduced cell proliferation. Taken together, our results show how MYC drives the production of specific eicosanoids critical for lung cancer cell survival and proliferation, with possible implications for the use of COX and LOX pathway inhibitors for lung cancer therapy. Cancer Res; 76(16); 4608-18. ©2016 AACR.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom. MRC Human Nutrition Research, Cambridge, United Kingdom.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Hall
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom. MRC Human Nutrition Research, Cambridge, United Kingdom.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Ament
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Catherine H
authors.initials: CH
authors.lastname: Wilson
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Burkhart
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Ashmore
authors.affiliation: MRC Human Nutrition Research, Cambridge, United Kingdom.
authors.forename: Albert
authors.initials: A
authors.lastname: Koulman
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Trevor
authors.initials: T
authors.lastname: Littlewood
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Gerard I
authors.initials: GI
authors.lastname: Evan
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom. MRC Human Nutrition Research, Cambridge, United Kingdom. jules.griffin@mrc-hnr.cam.ac.uk.
authors.forename: Julian L
authors.initials: JL
authors.lastname: Griffin
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000378:metabolism*; D007150:Immunohistochemistry; D050356:Lipid Metabolism / Q000502:physiology*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D016133:Polymerase Chain Reaction; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D015777:Eicosanoids; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)