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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 PET, desorption electrospray ionization-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 tumor 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 pharmacologic response. Significance: These findings demonstrate the translational potential of monitoring fatty acid uptake and identify lipoprotein lipase as a potential therapeutic target in melanoma.

Lipids play diverse roles in the body, including cell structure, cell signalling, and energy production; all of which are altered in cancer. Lipid metabolism is therefore a potential therapeutic target, and here has been investigated using a transgenic zebrafish model. This study combines transcriptome and lipidomic analyses for the first time, with in-vivo positron emission tomography (PET) and ex-vivo desorption electrospray ionisation-mass spectrometry (DESI-MS), to investigate lipid metabolism changes in melanoma. Most lipids are made of fatty acids, and the methods by which tumours acquire fatty acids can be altered compared to normal tissue. Here, the PET tracer [18F]-FTHA (a fatty acid analogue) has been used to demonstrate free fatty acid uptake in melanoma tumours in-vivo. Additionally, the excellent spatial resolution of mass spectrometry imaging has been utilised by imaging the FTHA ex-vivo by DESI-MS, allowing more precise spatial correlation with the histology, and revealing the heterogeneous nature of this fatty acid uptake. These imaging data complement the findings of the transcriptome analyses which show upregulation of genes associated with fatty acid uptake. Integrating transcriptome and lipidome data analyses revealed dysregulation of glycerophospholipid pathways, and was supported by DESI-MS data, which revealed heterogeneous changes in lipid metabolism. Citation Format: Fiona Henderson, Hannah Johnston, Emrys Jones, Duncan Foster, Raghavendar T. Nagaraju, Michael Green, Michael Fairclough, Irene Barinaga-Rementeria Ramirez, Shuning He, B.Ewa Snaar-Jagalska, Katherine A. Hollywood, Warwick Dunn, Herman P. Spaink, Paul Lorigan, Emmanuelle Claude, Kaye Williams, Adam Hurlstone, Adam McMahon. Multi-modality imaging to interrogate lipidome changes during melanoma progression in zebrafish [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4109.