Abstract
Simple SummaryMelanoma 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.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.
Highlights
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]
This conversion is catalyzed by ATP citrate lyase (ACLY), which is overexpressed in a variety of cancer types, including melanoma
Numerous studies showed that SL metabolism is dysregulated in melanoma cells, in order to reduce the intracellular level of ceramide, which is known to promote apoptosis
Summary
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]. Acetate dependence is specific to BRAF mutant but not NRAS mutant or wild-type tricarboxylic acid (TCA) cycle under normal conditions [4] This conversion is catalyzed by ATP citrate lyase (ACLY), which is overexpressed in a variety of cancer types, including melanoma. Increased ACLY expression was associated with poor outcome of patients with melanoma [5,6] During metabolic stress such as hypoxia, the synthesis of acetyl-CoA preferentially originates from acetate [7,8]. Low SCD expression and activity promoted ER stress and the phosphorylation of eukaryotic initiation factor-α (eIF2α) leading to the activation of an ATF4- and NF-κB-dependent inflammatory signaling that sustains a reduced MITF expression and melanoma cell dedifferentiation [49] These data demonstrate that FA metabolism can regulate melanoma cell differentiation and progression. 1-phosphate lyase; SPNS2, sphingolipid transporter 2; SPT, serine palmitoyltransferase; SR-BI, scavenger receptor class B type I; SREBP2, sterol regulatory element binding protein 2; S1P, sphingosine 1-phosphate; TAG, triacylglycerol; TCA, tricarboxylic acid
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