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Enhanced Fatty Acid Scavenging and Glycerophospholipid Metabolism Accompany Melanocyte Neoplasia Progression in Zebrafish Fiona Henderson1,2, Hannah R

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Enhanced Fatty Acid Scavenging and Glycerophospholipid Metabolism Accompany Melanocyte Neoplasia Progression in Zebrafish Fiona Henderson1,2, Hannah R Published OnlineFirst March 12, 2019; DOI: 10.1158/0008-5472.CAN-18-2409 Cancer Metabolism and Chemical Biology Research Enhanced Fatty Acid Scavenging and Glycerophospholipid Metabolism Accompany Melanocyte Neoplasia Progression in Zebrafish Fiona Henderson1,2, Hannah R. Johnston3, Andrew P. Badrock3, Emrys A. Jones4, Duncan Forster1, Raghavendar T. Nagaraju3, Christos Evangelou3, Jivko Kamarashev5, Michael Green1, Michael Fairclough1, Irene Barinaga-Rementeria Ramirez3, Shuning He6,7, B. Ewa Snaar-Jagalska6, Katherine Hollywood8, Warwick B. Dunn8,9, Herman P. Spaink6, Michael P. Smith3, Paul Lorigan10, Emmanuelle Claude4, Kaye J. Williams2, Adam W. McMahon1, and Adam Hurlstone3 Abstract Alterations in lipid metabolism in cancer cells impact cell rated by DESI-MS, which again revealed heterogeneous phos- structure, signaling, and energy metabolism, making lipid pholipid composition in tumors. Overexpression of the gene metabolism a potential diagnostic marker and therapeutic encoding lipoprotein lipase (LPL), which was upregulated in target. In this study, we combined PET, desorption electro- zebrafish melanocyte tumor nodules and expressed in the spray ionization-mass spectrometry (DESI-MS), nonimaging majority of human melanomas, accelerated progression of MS, and transcriptomic analyses to interrogate changes in oncogenic RAS-driven melanocyte neoplasia in zebrafish. lipid metabolism in a transgenic zebrafish model of onco- Depletion or antagonism of LPL suppressed human melanoma genic RAS-driven melanocyte neoplasia progression. Exoge- cell growth; this required simultaneous fatty acid synthase nous fatty acid uptake was detected in melanoma tumor (FASN) inhibition when FASN expression was also elevated. nodules by PET using the palmitic acid surrogate tracer Collectively, our findings implicate fatty acid acquisition as a 14(R,S)-18F-fluoro-6-thia-heptadecanoic acid ([18F]-FTHA), possible therapeutic target in melanoma, and the methods consistent with upregulation of genes associated with fatty acid we developed for monitoring fatty acid uptake have potential uptake found through microarray analysis. DESI-MS imaging for diagnosis, patient stratification, and monitoring pharma- revealed that FTHA uptake in tumors was heterogeneous. cologic response. Transcriptome and lipidome analyses further highlighted dys- regulation of glycerophospholipid pathways in melanoma Significance: These findings demonstrate the translational tumor nodules, including increased abundance of phosphati- potential of monitoring fatty acid uptake and identify lipo- dyl ethanolamine and phosphatidyl choline species, corrobo- protein lipase as a potential therapeutic target in melanoma. Introduction membrane components, signaling molecules, and also an energy Because of Otto Warburg's pioneering work, it has been rec- source for cells. Altered lipid metabolism is essential for cancer ognized that cancer cells undergo metabolic changes to sustain progression, with lipids playing a key role in cancer cell prolifer- their unbridled growth and dissemination. Lipids are major cell ation and metastasis. Moreover, lipidomics is generating insight 1Wolfson Molecular Imaging Centre, Division of Informatics, Imaging and Foundation Trust, The University of Manchester, Withington, Manchester, Data Sciences, School of Health Sciences, Manchester Academic Health United Kingdom. Science Centre, The University of Manchester, Manchester, United Kingdom. Note: Supplementary data for this article are available at Cancer Research 2Division of Pharmacy and Optometry, School of Health Sciences, Manche- Online (http://cancerres.aacrjournals.org/). ster Academic Health Science Centre, The University of Manchester, Man- chester, United Kingdom. 3Division of Cancer Sciences, School of Medical F. Henderson, H.R. Johnston, and A.P. Badrock contributed equally to this article. Sciences, Manchester Academic Health Science Centre, The University of K.J. Williams, A.W. McMahon, and A. Hurlstone are the co-senior authors of this Manchester, Manchester, United Kingdom. 4Waters Corporation, Wilmslow, article. United Kingdom. 5Department of Dermatology and Allergy, Universitats-€ Spital Zurich,€ Zurich,€ Switzerland. 6Institute of Biology, Leiden University, Corresponding Authors: Adam Hurlstone, The University of Manchester, Leiden, the Netherlands. 7Department of Pediatric Oncology, Dana-Farber Michael Smith Building, Rumofrod Street, Manchester M13 9PT, United Kingdom. Cancer Institute, Harvard Medical School, Boston, Massachusetts. 8Centre Phone: 4416-1275-1574; E-mail: [email protected]; and Adam for Advanced Discovery and Experimental Therapeutics (CADET), Central McMahon, Wolfson Molecular Imaging Centre, The University of Manchester, 27 Manchester University Hospitals NHS Foundation Trust, Manchester, United Palatine Road, Withington, Manchester M20 3LJ, United Kingdom. Phone: 4416- Kingdom. 9School of Biosciences, Institute of Metabolism and Systems 1275-0026; E-mail: [email protected] Research and Phenome Centre, University of Birmingham, Edgbaston, doi: 10.1158/0008-5472.CAN-18-2409 Birmingham, United Kingdom. 10Division of Cancer Sciences, School of Medical Sciences, Department of Medical Oncology, The Christie NHS Ó2019 American Association for Cancer Research. 2136 Cancer Res; 79(9) May 1, 2019 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst March 12, 2019; DOI: 10.1158/0008-5472.CAN-18-2409 Fatty Acid Uptake in Zebrafish Melanocyte Neoplasia into disease mechanisms and identifying new therapeutic tar- progresses to the metastatic stage. PET is able to image metabolic gets (1). While still sparse, emerging evidence implicates altered heterogeneity in vivo somewhat, however it is limited by low lipid metabolism in the development of melanoma too, with spatial resolution—in the low millimeter range, but exact resolu- alterations in the lipidome differentiating benign skin neoplasms tions vary depending on the scanner model and radioisotope from melanoma (2). used—and its targeted nature (defined by the tracer used). In Fatty acids are building blocks for complex lipids incorporated contrast to PET, desorption electrospray ionization mass spec- into membranes as well as substrates for b-oxidation, a major trometry (DESI-MS) imaging is an ambient ex vivo technique in energy-yielding reaction. How cancer cells obtain fatty acids is which a stream of charged microdroplets is directed onto a tissue altered compared with healthy tissue, although the exact mechan- section to generate gaseous ions from species on the section isms remain to be elucidated. Fatty acids can be synthesized de surface. These ions are then taken up into a mass spectrometer novo by the enzyme fatty acid synthase (FASN). FASN is over- inlet for analysis. Fatty acids and phospholipids ionize well by expressed in several cancers including melanoma (3, 4) and has DESI-MS, making it an ideal lipid imaging tool (22). DESI-MS has been the target of drug development programs over decades (5). the advantage of being an untargeted label-free technique, reveal- Although FASN inhibitors can antagonize the proliferation of ing the distribution of large numbers of lipids within a tissue cancer cell lines including melanoma cell lines (6, 7), they have section in one analysis at higher spatial resolution than achievable failed in the clinic due to insufficient efficacy and excessive by PET (<100 mm). Furthermore, tandem mass spectrometry toxicity (5). Fatty acids can also be scavenged from the blood (DESI-MS/MS) can be performed postimaging to identify indi- supply, or potentially acquired through close contact with adi- vidual lipid species. pocytes (8, 9). Fatty acid scavenging by fatty acid–binding protein Here, transcriptome profiling and nonimaging mass-spectrom- 7 (FABP7) has been associated with enhanced proliferation and etry–based metabolomics have been combined with PET and invasive capability of melanoma cells (10–12), while CD36- DESI-MS imaging modalities to investigate fatty acid uptake and mediated fatty acid scavenging is prominent in metastasis-initi- lipid metabolism in oncogenic RAS-driven zebrafish melanocyte ating melanoma cells (13). Furthermore, it was recently shown neoplasia. Transcriptome profiling identified a gene expression that FATP1/SLC27A1, which transports long-chain fatty acids into program associated with disease progression, which included cells, is enriched in melanoma compared with other cancer genes involved in fatty acid uptake and glycerophospholipid types (9), thereby highlighting the importance of fatty acid uptake metabolism. Enhanced fatty acid uptake was confirmed by both for melanoma progression. PET and DESI-MS imaging of FTHA. DESI-MS and conventional The small domesticated fish, Xiphophorus, medaka, and zeb- mass spectrometry also confirmed enhanced glycerophospholi- rafish, have been used for modeling melanoma since (in the pid metabolism. DESI-MS provided insight into tumor hetero- case of Xiphophorus) the early decades of the last century. geneity in lipid metabolism. The product of one disease progres- Melanocyte tumors arising in these models show comparable sion–associated gene, lipoprotein lipase (LPL), implicated in fatty histopathology and molecular signatures to human melanoma acid scavenging (23), was found to be expressed in a majority of due to the conservation of skin structures, melanocyte devel- human melanoma cell lines and tumor samples. LPL depletion
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