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

Henderson, F., Johnston, H.R., Badrock, A.P., Jones, E.A., Forster, D., Nagaraju, R.T., Evangelou, C., Kamarashev, J., Green, M., Fairclough, M., Barinaga-Rementeria Ramirez, I., He, S., Snaar-Jagalska, B.E., Hollywood, K., Dunn, W.B., Spaink, H.P., Smith, M.P., Lorigan, P., Claude, E., Williams, K.J., McMahon, A.W., Hurlstone, A.
Cancer research   79(9): 2136-2151 (Journal)
Registered Authors
Badrock, Andrew P., He, Shuning, Hurlstone, Adam, Snaar-Jagalska, Ewa B., Spaink, Herman P.
MeSH Terms
  • Animals
  • Energy Metabolism
  • Fatty Acid Synthases/genetics
  • Fatty Acid Synthases/metabolism
  • Fatty Acids/metabolism*
  • Glycerophospholipids/metabolism*
  • Humans
  • Lipoprotein Lipase/genetics
  • Lipoprotein Lipase/metabolism
  • Melanocytes/metabolism
  • Melanocytes/pathology*
  • Melanoma/genetics
  • Melanoma/metabolism
  • Melanoma/pathology*
  • Metabolomics
  • Microphthalmia-Associated Transcription Factor/genetics
  • Transcriptome
  • Tumor Cells, Cultured
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • Zebrafish Proteins/genetics
  • ras Proteins/genetics
  • ras Proteins/metabolism
30862716 Full text @ Cancer Res.
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), non-imaging 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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes