Metabolic Plasticity of Melanoma Cells and Their Crosstalk With Tumor Microenvironment

Abstract

Cutaneous melanoma (CM) is a highly aggressive and drug resistant solid tumor, showing an impressive metabolic plasticity modulated by oncogenic activation. In particular, melanoma cells can generate adenosine triphosphate (ATP) during cancer progression by both cytosolic and mitochondrial compartments, although CM energetic request mostly relies on glycolysis. The upregulation of glycolysis is associated with constitutive activation of BRAF/MAPK signaling sustained by BRAF^V600E kinase mutant. In this scenario, the growth and progression of CM are strongly affected by melanoma metabolic changes and interplay with tumor microenvironment (TME) that sustain tumor development and immune escape. Furthermore, CM metabolic plasticity can induce a metabolic adaptive response to BRAF/MEK inhibitors (BRAFi/MEKi), associated with the shift from glycolysis toward oxidative phosphorylation (OXPHOS). Therefore, in this review article we survey the metabolic alterations and plasticity of CM, its crosstalk with TME that regulates melanoma progression, drug resistance and immunosurveillance. Finally, we describe hallmarks of melanoma therapeutic strategies targeting the shift from glycolysis toward OXPHOS.

Keywords: OXPHOS; cutaneous melanoma; metabolic alterations; therapeutic strategies; tumor microenvironment.

Figure 1

Warburg effect in melanoma cells caused by BRAF^V600E mutation leading to constitutive activation of MAPK pathway. Arrows indicate activation and T-bars show inhibition. Dotted red arrows, also indicated by a “red X,” symbolize inactive pathways, while solid T-bars and arrows indicate active signaling during Warburg effect.

Figure 2

Alterations of cancer and immune cells associated with melanoma microenvironment acidification. Hypoxia (caused by increasing distance from tumor vessels, structural abnormalities of tumor vasculature and high cancer cell O₂ consumption) and genetic mutations (such as BRAF^V600E, loss of PTEN, etc.) trigger a metabolic reprogramming in melanoma cells, which increase glycolysis. Glycolytic melanoma cells promote an abnormal extracellular accumulation of lactate and protons and thus induce the acidification of TME. In turn, the acidic TME triggers a metabolic reprogramming in melanoma cells, which increase OXPHOS and decrease glycolysis. Additionally, tumor acidity increases melanoma malignancy by enhancing the migratory and invasive capability of melanoma cells and their capability to produce proteases (such as MMP-2/9, cathepsin, etc.) and pro-angiogenic factors (such as VEGF-A, IL-8, etc.). Acidity generates an immunosuppressive milieu, where T cells and NK cells lose their cytotoxic activity, and macrophages acquire the protumorigenic M2-like phenotype. Also glycolytic melanoma cells contribute to the generation of this immunosuppressive environment. In fact, by mediating glucose restriction, melanoma cells alter T cell metabolism and reduce their cytotoxic activity. Therefore, the pH and oxygen gradients in the tumor mass lead to molecular and metabolic changes in cancer and immune cells, which work together and cooperate to sustain melanoma progression.