Enhanced Fatty Acid Scavenging and Glycerophospholipid Metabolism Accompany Melanocyte Neoplasia Progression in Zebrafish

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 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.

In Vivo Optical Metabolic Imaging of Long-Chain Fatty Acid Uptake in Orthotopic Models of Triple-Negative Breast Cancer

“…The most common in vivo metabolic imaging modality currently used for metabolic imaging is FDG-PET to measure glucose uptake with a radiolabeled glucose tracer [20]. Previous studies outside of breast cancer have validated the use of an additional radio-labeled PET tracer, 18F-fluoro-6-thia-heptadecanoic acid (18F-FTHA), for in vivo fatty acid uptake measurements for myocardium imaging [21], and, more recently, for prostate cancer [22] and melanoma [23]. Though metabolic imaging through PET has proved valuable, especially in the clinic, its millimeter-scale resolution prevents capture of tumor heterogeneity [24,25], which tend to be under 1 cm in diameter.…”

Identification of F5 as a Prognostic Biomarker in Patients with Gastric Cancer

“…Inhibition of glycerophospholipid biosynthesis by a key enzyme of lysophosphatidic acid acyltransferase β (LPAAT-β) may be a potential therapeutic target for osteosarcoma patients [34]. Henderson et al found that glycerophospholipid metabolism is enhanced in melanocyte neoplasia in zebrafish where it accelerates tumour progression [35]. Enrichment analysis results show that biosynthesis and metabolism of glycerophospholipids are among the biological pathways involved in cancer progression.…”

Lipid metabolic Reprogramming: Role in Melanoma Progression and Therapeutic Perspectives

“…Interestingly, it was reported that melanoma-derived microvesicles favor the establishment of metastasis in a PS-dependent manner, possibly by downregulating the host's inflammatory immune responses [59]. Moreover, lipidome analyses revealed aberrant GPL metabolism with increased levels of PE and PC species in zebrafish V12RAS-driven melanoma [60]. Importantly, several studies have shown that cancer cells undergoing EMT have increased PC content and that phosphatidic acid (PA), a key intermediate metabolite in the synthesis of GPL, could maintain the stemness of cancer cells, by reducing apoptosis [61].…”