Lipid metabolic Reprogramming: Role in Melanoma Progression and Therapeutic Perspectives

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.

Glioma glycolipid metabolism: MSI2–SNORD12B–FIP1L1–ZBTB4 feedback loop as a potential treatment target

“…2 Reprogramming of energy metabolism is an important indicator of malignant tumors. [3][4][5] Abnormal energy metabolism has also been reported in GBM and includes enhanced aerobic glycolysis and lipid synthesis to provide energy and raw materials to the highly proliferating cells. [6][7][8][9] Thus, key glycolipid metabolic enzymes and transcription factors are considered promising treatment targets and diagnostic and prognostic tumor markers for predictive, preventive, and personalized medicine.…”

“…The median survival time of GBM patients is approximately 12–15 months 2 . Reprogramming of energy metabolism is an important indicator of malignant tumors 3–5 . Abnormal energy metabolism has also been reported in GBM and includes enhanced aerobic glycolysis and lipid synthesis to provide energy and raw materials to the highly proliferating cells 6–9 .…”

Targeted Metabolomics Identifies Plasma Biomarkers in Mice with Metabolically Heterogeneous Melanoma Xenografts

“…Metabolite profiling of different melanoma xenografts revealed highly distinct lipid profiles. Emerging evidence supports the importance of lipid metabolism in melanoma progression since many alterations of the lipid metabolic network contributing to sustained cell proliferation and melanoma metastasis have been reported [ 21 ]. Lipids constitute an important energy source for cells but are also structural components of cellular membranes.…”

“…Increased lipolysis and β-oxidation have been associated with melanoma progression [ 21 , 27 , 28 ]. Most ACs were found to be higher in WM47 and WM3000 compared to A375 and WM3311 xenografts, indicating increased β-oxidation in WM47 and WM3000 melanomas.…”

“…Moreover, glutamine can support fatty acid (FA) synthesis in melanoma cells by running the TCA cycle in the reverse direction [ 20 ]. Dysregulation of lipid metabolism, including various alterations in FA metabolism, has been associated with melanoma growth and aggressiveness [ 21 ]. Fatty acid synthase (FASN), the rate limiting enzyme in FA synthesis, is upregulated in many cancer types, including melanoma, due to constitutive activation of the transcription factor sterol regulatory element-binding protein 1c (SREBP1c) driven by the MAPK and PI3K/AKT pathways [ 22 , 23 , 24 , 25 ].…”