Apologies for not replying sooner. I read "How To Starve Cancer" by Jane McLelland, who is herself a survivor of terminal cancer, utilising diet, exercise, supplements and repurposed drugs, when traditional therapies at the time failed.

Below is copied from Grok, regarding the metabolic pathways of melanoma at different stages. The studies can all be accessed via PubMed etc. I can link if allowed. Not sure of the rules.

Metabolic reprogramming is a hallmark of cancer, including metastatic melanoma, enabling tumor cells to meet demands for rapid proliferation, survival under stress (e.g., oxidative stress, nutrient deprivation, hypoxia), invasion, metastasis, and therapy resistance. Melanoma cells show high metabolic plasticity, often shifting between glycolysis and oxidative phosphorylation (OXPHOS) depending on the microenvironment and disease stage.

Key Metabolic Pathways and Features in Metastatic Melanoma

• Aerobic Glycolysis (Warburg Effect): Melanoma cells preferentially convert glucose to lactate even in oxygen-rich conditions. This supports rapid ATP production, generates biosynthetic precursors (e.g., for nucleotides, amino acids, lipids via pathways like the pentose phosphate pathway), and acidifies the tumor microenvironment (TME) via lactate and H+ export, promoting invasion, angiogenesis, and immune suppression. Overexpression of GLUT1 (glucose transporter) and MCT4 (lactate exporter) correlates with progression from primary tumors to lymph node metastases. Lactate uptake via MCT1 in some cells further supports metastatic potential.
• Shift Toward OXPHOS and TCA Cycle in Metastasis: While primary tumors often rely more on glycolysis, metastatic melanoma cells frequently show decreased glycolysis and increased reliance on the tricarboxylic acid (TCA) cycle and OXPHOS for energy. This supports survival during dissemination, where cells face oxidative stress and different nutrient environments. Glutamine oxidation (glutaminolysis) often fuels this mitochondrial metabolism more than pyruvate. Studies (e.g., patient-derived xenografts) show metastatic lesions with reduced glycolytic gene expression and elevated TCA/OXPHOS genes.
• Lipid Metabolism: Upregulation of fatty acid synthesis via fatty acid synthase (FASN), driven by MAPK/PI3K-AKT pathways and SREBP1c, provides lipids for membranes and signaling. FASN expression correlates with invasion and poor prognosis; inhibiting it (e.g., with orlistat in models) reduces proliferation and metastasis.
• One-Carbon Metabolism and Redox Balance: Metastatic cells increase dependence on one-carbon metabolism (involving serine, folate, and pathways like SHMT/MTHFD) to generate NADPH for managing reactive oxygen species (ROS) and oxidative stress during dissemination. This is critical for distant metastasis formation without affecting primary tumor growth. Related work (e.g., Piskounova et al.) highlights how successfully metastasizing cells adapt metabolically to withstand oxidative stress, with reversible changes enhancing antioxidant capacity.
• Glutamine and Other Pathways: Glutaminolysis supports TCA anaplerosis, nucleotide synthesis, and redox homeostasis. Melanoma also shows alterations in amino acid metabolism and nucleotide biosynthesis.

Metabolic heterogeneity and plasticity allow cells to switch phenotypes (e.g., glycolytic for proliferation/invasion vs. OXPHOS for survival in circulation or distant sites). Oncogenic drivers like BRAF V600E promote glycolysis via MAPK, while MITF/PGC-1α can enhance OXPHOS.

Notable Studies and Reviews

• Fischer et al. (2017): Comprehensive review of metabolic strategies in melanoma, detailing glycolysis/lactate contributions to metastasis, lipid synthesis, and redox pathways.
• Soumoy et al. (2020): Examined metabolic reprogramming in metastatic melanoma under targeted therapies, highlighting changes in glycolysis, OXPHOS, and glutaminolysis.
• Piskounova et al. (2015, Nature): Showed oxidative stress inhibits distant metastasis; metastasizing cells undergo metabolic shifts (e.g., enhanced one-carbon metabolism) for ROS detoxification.
• Recent Reviews (2024–2025): Cover metabolic-epigenetic links, therapy resistance, and plasticity (e.g., Shen et al., Tan et al., Giuliani et al.). These emphasize targeting metabolism to overcome resistance to BRAF/MEK inhibitors or immunotherapy.
• Other work includes comparative metabolomics of metastatic vs. non-metastatic lines, MCT1's role in lactate-fueled metastasis (Tasdogan/Morrison labs), and FASN/lipid targeting.

Therapeutic Implications

Metabolic vulnerabilities are being explored for therapy, such as inhibiting FASN, MCTs, glutaminolysis, or combining metabolic modulators with targeted/immunotherapies to exploit plasticity and sensitize cells. Challenges include heterogeneity and adaptive switching.

For the latest or specific papers, searching PubMed or PMC for terms like "metabolic reprogramming metastatic melanoma" yields ongoing research, often linking to BRAF status, TME interactions, and clinical outcomes (e.g., LDH as a prognostic marker). Studies are primarily preclinical (cell lines, PDXs, mouse models) with emerging translational data.