cancers Review Lipid metabolic Reprogramming: Role in Melanoma Progression and Therapeutic Perspectives 1, 1, 1 2 1 Laurence Pellerin y, Lorry Carrié y , Carine Dufau , Laurence Nieto , Bruno Ségui , 1,3 1, , 1, , Thierry Levade , Joëlle Riond * z and Nathalie Andrieu-Abadie * z 1 Centre de Recherches en Cancérologie de Toulouse, Equipe Labellisée Fondation ARC, Université Fédérale de Toulouse Midi-Pyrénées, Université Toulouse III Paul-Sabatier, Inserm 1037, 2 avenue Hubert Curien, tgrCS 53717, 31037 Toulouse CEDEX 1, France; [email protected] (L.P.); [email protected] (L.C.); [email protected] (C.D.); [email protected] (B.S.); [email protected] (T.L.) 2 Institut de Pharmacologie et de Biologie Structurale, CNRS, Université Toulouse III Paul-Sabatier, UMR 5089, 205 Route de Narbonne, 31400 Toulouse, France; [email protected] 3 Laboratoire de Biochimie Métabolique, CHU Toulouse, 31059 Toulouse, France * Correspondence: [email protected] (J.R.); [email protected] (N.A.-A.); Tel.: +33-582-7416-20 (J.R.) These authors contributed equally to this work. y These authors jointly supervised this work. z Received: 15 September 2020; Accepted: 23 October 2020; Published: 27 October 2020 Simple Summary: Melanoma is a devastating skin cancer characterized by an impressive metabolic plasticity. Melanoma cells are able to adapt to the tumor microenvironment by using a variety of fuels that contribute to tumor growth and progression. In this review, the authors summarize the contribution of the lipid metabolic network in melanoma plasticity and aggressiveness, with a particular attention to specific lipid classes such as glycerophospholipids, sphingolipids, sterols and eicosanoids. They also highlight the role of adipose tissue in tumor progression as well as the potential antitumor role of drugs targeting critical steps of lipid metabolic pathways in the context of melanoma. Abstract: Metabolic reprogramming contributes to the pathogenesis and heterogeneity of melanoma. It is driven both by oncogenic events and the constraints imposed by a nutrient- and oxygen-scarce microenvironment. Among the most prominent metabolic reprogramming features is an increased rate of lipid synthesis. Lipids serve as a source of energy and form the structural foundation of all membranes, but have also emerged as mediators that not only impact classical oncogenic signaling pathways, but also contribute to melanoma progression. Various alterations in fatty acid metabolism have been reported and can contribute to melanoma cell aggressiveness. Elevated expression of the key lipogenic fatty acid synthase is associated with tumor cell invasion and poor prognosis. Fatty acid uptake from the surrounding microenvironment, fatty acid β-oxidation and storage also appear to play an essential role in tumor cell migration. The aim of this review is (i) to focus on the major alterations affecting lipid storage organelles and lipid metabolism. A particular attention has been paid to glycerophospholipids, sphingolipids, sterols and eicosanoids, (ii) to discuss how these metabolic dysregulations contribute to the phenotype plasticity of melanoma cells and/or melanoma aggressiveness, and (iii) to highlight therapeutic approaches targeting lipid metabolism that could be applicable for melanoma treatment. Keywords: cancer; cholesterol; eicosanoid; fatty acid; glycerophospholipid; lipid droplet; metastasis; obesity; phenotypic switch; pseudo-EMT; sphingolipid Cancers 2020, 12, 3147; doi:10.3390/cancers12113147 www.mdpi.com/journal/cancers Cancers 2020, 12, 3147 2 of 33 1. Introduction The metabolic remodeling is a crucial process that allows melanoma cells to adapt to tumor microenvironment (TME) and to sustain growth and dissemination [1,2]. A comparative metabolic flux profiling of melanoma cell lines and normal melanocytes showed that all melanoma cells consumed more glucose and produced more lactate than melanocytes [3]. Interestingly, emerging evidence reported numerous alterations of the lipid metabolic network that couldCancers sustain 2020, 12 cell, x growth and metastasis in melanoma cells (Figure1). 2 of 33 glucose Plasma membrane Lipid rafts mitochondrion acetyl-CoA 3 glucose gangliosides SM TCA FAO cycle serine citrate G3P 5 6 GPL Sphingolipid fatty acyl-CoA LPA acetate citrate synthesis synthesis S1P acetate PA PI receptors Ceramide TAG DAG PC, PE, PS S1P S1P acetyl-CoA aceto acetyl-CoA FA synthesis 7 9 PGE2 receptors palmitic acid Cholesterol PGE2 synthesis synthesis 1 FA 4 Mevalonate PGE desaturation 2 PGE2 Lipid droplets Other FA cholesterol MAG TAG FA CE Oxysterols AA Dendrogenin A FA PUFA 8 FA Cholesterol PL 2 import import FA extracellular Lipid rafts vesicle ADIPOCYTE Figure 1.FigureSchematic 1. Schematic overview overview of theof the lipid lipid metabolic metabolic ne networktwork that that regulates regulates melanoma melanoma progression. progression. The figureThe highlights figure highlights the lipidthe lipid pathways pathways that that are are mostly mostly altered altered in melanoma in melanoma cells: (1) the cells: de novo (1) the de novo synthesis,synthesis, elongation elongation and and desaturation desaturation of fatty of fattyacids (FA), acids which (FA), produce which the produce repertoire the of repertoire FA with of FA different saturation levels. (2) The import of FA from neighboring adipocytes that can fuel FA β- with different saturation levels. (2) The import of FA from neighboring adipocytes that can fuel oxidation (FAO) in mitochondria (3) to produce energy. (4) The lipid droplets, composed of neutral FA β-oxidationlipids, i.e., (FAO) triacylglycerol in mitochondria (TAG) and ( 3cholesteryl) to produce ester energy.(CE), which (4) are The critical lipid to droplets, melanoma composed cell of neutral lipids,aggressiveness. i.e., triacylglycerol (5) The synthesis (TAG) of and glycerophospholipids cholesteryl ester (GPL), (CE), whichincluding are phosphatidylcholine critical to melanoma cell aggressiveness.(PC), phosphatidylethanolamine (5) The synthesis of glycerophospholipids (PE,) phosphatidylserine (PS) (GPL), and includingphosphatidylinositol phosphatidylcholine (PI), which (PC), phosphatidylethanolamineare produced from glycerol-3-phosphate (PE,) phosphatidylserine (G3P). (6) The (PS)synthesis and of phosphatidylinositol sphingolipids, which begins (PI), with which are the condensation of serine and FA-Coenzyme A conjugates. Sphingolipids and glyceroPL are produced from glycerol-3-phosphate (G3P). (6) The synthesis of sphingolipids, which begins with the precursors of lipid mediators involved in cell signaling pathways and are used to build cell condensationmembranes of serine in order and to FA-Coenzyme sustain cancer cell A conjugates.proliferation. Sphingolipids(7) The cholesterol and biosynthesis, glyceroPL initiated are precursors by of lipid mediatorsthe conversion involved of acetyl-CoA in cell signalingto acetoacetyl-CoA, pathways and ( and8) the are cholesterol used to import build from cell the membranes bloodstream. in order to sustainCholesterol cancer cell and proliferation.sphingolipids, i.e., (7 sphingomyelin) The cholesterol (SM) and biosynthesis, gangliosides, initiated are part of by the the lipid conversion rafts, of acetyl-CoAwhich to act acetoacetyl-CoA, as signaling hubs in and cancer (8) cell the proliferation, cholesterol adhesion import and from migration. the bloodstream. (9) The synthesis Cholesterol of prostaglandin E2 (PGE2) from arachidonic acid (AA), a long-chain polyunsaturated FA (PUFA) freed and sphingolipids, i.e., sphingomyelin (SM) and gangliosides, are part of the lipid rafts, which act as from phospholipids (PL). PGE2 and the sphingolipid metabolite S1P are secreted and act through cell signalingsurface hubs in receptors cancer to cell suppress proliferation, immune adhesionresponse an andd promote migration. melanoma (9) The progression. synthesis Abbreviations: of prostaglandin E2 (PGE2) fromLPA, arachidonic lysophosphatidic acid acid; (AA), MAG, a long-chain monoacylglycerol polyunsaturated; PA, phosphatidic FA (PUFA) acid; TCA, freed tricarboxylic from phospholipids acid. (PL). PGE2 and the sphingolipid metabolite S1P are secreted and act through cell surface receptors to suppressThe immune most responseprominent and phenomenon promote melanoma is an increased progression. rate of lipogenesis, Abbreviations: in which LPA, nutrient-derived lysophosphatidic acid;carbons MAG, monoacylglycerol;get converted into fatty PA, acids phosphatidic (FAs), sterol acid;s and TCA, complex tricarboxylic lipids. Lipogenesis acid. relies mainly on the availability of acetyl-CoA. The main precursor of cytosolic acetyl-CoA is citrate originating from the tricarboxylic acid (TCA) cycle under normal conditions [4]. This conversion is catalyzed by ATP The most prominent phenomenon is an increased rate of lipogenesis, in which nutrient-derived citrate lyase (ACLY), which is overexpressed in a variety of cancer types, including melanoma. carbons getMoreover, converted increased into ACLY fatty expression acids (FAs), was sterolsassociated and with complex poor outcome lipids. of Lipogenesispatients with melanoma relies mainly on the availability[5,6]. During of acetyl-CoA. metabolic stress The mainsuch as precursor hypoxia, the of cytosolicsynthesis of acetyl-CoA acetyl-CoA ispreferentially citrate originating originates from the from acetate [7,8]. Acetate dependence is specific to BRAF mutant but not NRAS mutant or wild-type Cancers 2020, 12, 3147 3 of 33 tricarboxylic