TY - JOUR
T1 - Enhanced fatty acid scavenging and glycerophospholipid metabolism accompanies melanocyte neoplasia progression in zebrafish
AU - Henderson, Fiona
AU - Johnston, Hannah
AU - Badrock, Andrew
AU - Jones, Emrys
AU - Forster, Duncan
AU - Nagaraju, Raghavendar
AU - Evangelou, Christos
AU - Kamarashev, Jivko
AU - Green, Michael
AU - Fairclough, Michael
AU - Barinaga-Rementeria, Irene
AU - He, Shuning
AU - Jagalska, Ewa Snaar
AU - Hollywood, Katherine
AU - Dunn, Warwick
AU - Spaink, Herman P.
AU - Smith, Michael
AU - Lorigan, Paul
AU - Claude, Emmanuelle
AU - Williams, Kaye
AU - Mcmahon, Adam
AU - Hurlstone, Adam
N1 - Funding Information:
P. Lorigan reports receiving a commercial research grant and other commercial research support from BMS; has received speakers bureau honoraria from BMS, MSD, and Novartis; and is a consultant/advisory board member for BMS, MSD, Pierre Fabre, and Novartis. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
The authors like to thank Paul Begley for his technical support. The work was supported by the European Research Council (grant no. ERC-2011-StG-282059 PROMINENT to A. Hurlstone) and by the Cancer Research UK (CRUK) and Engineering and Physical Sciences Research Council (EPSRC) Manchester and Cambridge Cancer Imaging Centre (grant no. C8742/A18097 to K.J. Williams and A.W. McMahon). H.R. Johnston was funded by a BBSRC Ph.D studentship and Christie Charity Award. F. Henderson was funded by a BBSRC PhD studentship.
Publisher Copyright:
© 2019 American Association for Cancer Research.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2019/3/12
Y1 - 2019/3/12
N2 - 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), 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 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.
AB - 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), 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 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.
KW - Mass Spectrometry Imaging,
KW - Lipid Metabolism
KW - Transcriptome Analysis
KW - LPL
KW - Fatty Acid
U2 - 10.1158/0008-5472.can-18-2409
DO - 10.1158/0008-5472.can-18-2409
M3 - Article
SN - 0008-5472
VL - 79
SP - 2136
EP - 2151
JO - Cancer Research
JF - Cancer Research
IS - 9
ER -