Metabolic Reprogramming in Melanoma Cells

Melanoma cells exhibit pronounced metabolic plasticity that underpins their rapid proliferation, invasion and resistance to therapy. While many tumours rely on aerobic glycolysis to fulfil bioenergetic and biosynthetic needs, melanoma adapts dynamically by engaging oxidative phosphorylation, fatty acid oxidation and glutamine-driven anaplerosis. Oncogenic drivers such as BRAF and NRAS mutations orchestrate shifts between glycolytic and mitochondrial programmes, enabling melanoma cells to survive under nutrient scarcity, oxidative stress and targeted inhibition. Furthermore, interactions with the tumour microenvironment reinforce metabolic rewiring, modulating immune evasion and metastatic competence. Therapeutic resistance often coincides with secondary metabolic adaptations, including enhanced lipid utilisation, altered amino acid metabolism and epigenetic remodelling of metabolic gene networks. Understanding these intertwined pathways has unveiled vulnerabilities that form the basis for novel combinatorial strategies to overcome resistance and improve patient outcomes.

Research from Nature Portfolio

Recent studies have shown that prolonged treatment with BRAF inhibitors induces a switch towards fatty acid oxidation, which contributes to acquired resistance. Repurposing the anti-anginal drug ranolazine to inhibit fatty acid oxidation and concurrently rewire the methionine salvage pathway enhances antigen presentation and interferon signalling, thereby sensitising resistant melanoma to both targeted therapy and immune checkpoint blockade. This dual metabolic and immunogenic modulation significantly delays tumour recurrence and boosts antitumour immunity.

Foundational lipidomic and metabolomic profiling across melanoma cell lines of varying metastatic potential has identified aminomalonic acid and distinct phosphatidylinositol species as biomarkers of aggressive disease. These analyses revealed progressive alterations in lipid composition that correlate with invasive behaviour, establishing metabolic lipid signatures as both diagnostic markers and therapeutic targets to restrict melanoma dissemination.

Metabolic Reprogramming in Melanoma Cells publication trend

The graph below shows the total number of articles in metabolic reprogramming in melanoma cells across all publications each year (not limited to Nature Index journals).

Technical terms

Metabolic reprogramming: the process by which cancer cells alter their energy-producing and biosynthetic pathways to support growth and stress adaptation.

Glycolysis: a cytosolic pathway converting glucose into pyruvate, generating ATP and lactate.

Oxidative phosphorylation (OXPHOS): mitochondrial generation of ATP via the electron transport chain and chemiosmotic coupling.

Fatty acid oxidation (FAO): mitochondrial breakdown of fatty acids into acetyl-CoA for energy production.

TCA cycle: a sequence of mitochondrial reactions that oxidise acetyl-CoA to produce reducing equivalents for OXPHOS.

Anaplerosis: replenishment of TCA cycle intermediates through pathways such as glutamine metabolism.

Methionine salvage pathway: a route that recycles methylthioadenosine to regenerate methionine, supporting methylation and redox balance.

Lipidomic profiling: systematic analysis of cellular lipid species to identify alterations in membrane composition and signalling lipids.

Single-cell RNA-sequencing: a technique that measures gene expression at the individual cell level, revealing cellular heterogeneity.

References

1. Metabolic rewiring induced by ranolazine improves melanoma responses to targeted therapy and immunotherapy. Nature Metabolism (2023).
2. TFEB inhibition induces melanoma shut-down by blocking the cell cycle and rewiring metabolism. Cell Death & Disease (2023).
3. Metabolic Plasticity of Melanoma Cells and Their Crosstalk With Tumor Microenvironment. Frontiers in Oncology (2020).
4. Comparative Metabolic Flux Profiling of Melanoma Cell Lines BEYOND THE WARBURG EFFECT*. Journal of Biological Chemistry (2011).
5. Discovery of potential biomarkers in human melanoma cells with different metastatic potential by metabolic and lipidomic profiling. Scientific Reports (2017).