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

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

Publication date: Mar 12, 2019

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.

Henderson, F., Johnston, H.R., Badrock, A.P., Jones, E.A., Forster, D., Nagaraju, R.T., Evangelou, C., Kamarashev, J., Green, M., Fairclough, M., Ramirez, Barinaga-Rementeria, 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., and Hurlstone, A. Enhanced fatty acid scavenging and glycerophospholipid metabolism accompanies melanocyte neoplasia progression in zebrafish. 21953. 2019 Cancer Res.

Concepts Keywords
Desorption Melanoma tumor
Electrospray Majority melanomas
Fatty Acid MS
Fatty Acid Synthase Tumor
Glycerophospholipid Imaging
Glycerophospholipid Metabolism Tomography
Ionisation DNA Chip
Lipid Metabolism FASN
Lipoprotein Lipase Lipid metabolism
Mass Spectrometry Zebrafish
Melanocyte Stem cell research
Melanoma Regenerative biomedicine
Melanomas Lipids
Metabolism Danio
Microarray Branches of biology
Neoplasia FTHA uptake tumors
Nodules Zebrafish melanocyte tumor
Oncogenic Tumors
Palmitic Acid
PET
Pharmacological
Phosphatidyl Choline
Phosphatidyl Ethanolamine
Phospholipid
Positron Emission Tomography
RAS
Scavenging
Species
Stratification
Tracer
Transcriptome
Transcriptomic
Transgenic
Tumor
Tumour
Zebrafish

Semantics

Type Source Name
disease MESH diagnosis
gene UNIPROT FASN
gene UNIPROT LCP1
gene UNIPROT LPL
drug DRUGBANK Choline
drug DRUGBANK Ethanolamine
drug DRUGBANK Palmitic Acid
pathway BSID Melanoma
disease DOID melanoma
disease MESH melanoma
gene UNIPROT DESI2
drug DRUGBANK Rasagiline
gene UNIPROT FBN1
pathway BSID Metabolism
gene UNIPROT IMPACT
disease DOID cancer
disease MESH neoplasia
pathway BSID Glycerophospholipid metabolism

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