Enhanced fatty acid scavenging and glycerophospholipid metabolism accompanies melanocyte neoplasia progression in zebrafish

Fiona Henderson, Hannah Johnston, Andrew Badrock, Emrys Jones, Duncan Forster, Raghavendar Nagaraju, Christos Evangelou, Jivko Kamarashev, Michael Green, Michael Fairclough, Irene Barinaga-Rementeria, Shuning He, Ewa Snaar Jagalska, Katherine Hollywood, Warwick Dunn, Herman P. Spaink, Michael Smith, Paul Lorigan, Emmanuelle Claude, Kaye WilliamsAdam Mcmahon, Adam Hurlstone

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Abstract

Alterations in lipid metabolism in cancer cells impact cell structure, signaling, and energy metabolism, making lipid metabolism a potential diagnostic marker and therapeutic target. In this study, we combined positron emission tomography (PET), desorption electrospray ionisation-mass spectrometry (DESI-MS), nonimaging MS, and transcriptomic analyses to interrogate changes in lipid metabolism in a transgenic zebrafish model of oncogenic RAS-driven melanocyte neoplasia progression. Exogenous fatty acid uptake was detected in melanoma tumor nodules by PET using the palmitic acid surrogate tracer 14(R,S)-18F-fluoro-6- thia-heptadecanoic acid ([18F]-FTHA), consistent with upregulation of genes associated with fatty acid uptake found through microarray analysis. DESI-MS imaging revealed that FTHA uptake in tumors was heterogeneous. Transcriptome and lipidome analyses further highlighted dysregulation of glycerophospholipid pathways in melanoma tumour nodules, including increased abundance of phosphatidyl ethanolamine and phosphatidyl choline species, corroborated by DESI-MS which again revealed heterogeneous phospholipid composition in tumors. Overexpression of the gene encoding lipoprotein lipase (LPL), which was upregulated in zebrafish melanocyte tumor nodules and expressed in the majority of human melanomas, accelerated progression of oncogenic RAS-driven melanocyte neoplasia in zebrafish. Depletion or antagonism of LPL suppressed human melanoma cell growth; this required simultaneous fatty acid synthase (FASN) inhibition when FASN expression was also elevated. Collectively, our findings implicate fatty acid acquisition as a possible therapeutic target in melanoma, and the methods we developed for monitoring fatty acid uptake have potential for diagnosis, patient stratification, and monitoring pharmacological response.
Original languageEnglish
Pages (from-to)2136-2151
Number of pages16
JournalCancer Research
Volume79
Issue number9
DOIs
Publication statusPublished - 12 Mar 2019

Keywords

  • Mass Spectrometry Imaging,
  • Lipid Metabolism
  • Transcriptome Analysis
  • LPL
  • Fatty Acid

Research Beacons, Institutes and Platforms

  • Manchester Institute of Biotechnology

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