Glycolysis and OXPHOS balance in metastatic melanoma. (A) The cartoon serves to illustrate our hypothesis that in melanoma patients with normal serum LDH, equilibrium exists between glycolysis and OXPHOS, whereas in melanoma patients with high serum LDH, this balance shifts more towards glycolysis. In the center (indicated by the color red) of a melanoma that is more distant from the blood supply (indicated by the color green), the resulting hypoxia and thus, upregulation of a HIF-1α-dependent glycolytic program is taking up a larger portion of the tumor. (B) In patients with metastatic melanoma and normal serum LDH, glycolysis (indicated by red arrows) and OXPHOS (indicated by green arrows) are both utilized by melanoma cells. Excess H+ due to lactate production from glycolysis is extruded predominantly by MCT4. In larger size tumors from patients with metastatic melanoma and high serum LDH, two additional populations are emerging due to increasing distance of the tumor’s center from blood supply.