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Figure 11. Multifactorial reprogramming to acidification of melanoma tumor microenvironment. The pH and oxygen microenvironment
work together with genetic and metabolic pathways to promote melanoma proliferation and metastasis progression [176] . HIF-1α:
hypoxia-inducible factor-1 alpha; mTOR: mammalian target of rapamycin

MMPs degrading extracellular matrix and allowing for openings for cells to invade neighboring tissues [174] .
HIF-1α initiates VEGF-A expression and key to downregulating mitochondrial energy metabolism by
switching to glycolysis [163] . This Warburg effect of lactic acidosis contributes to the acidification of the tumor
microenvironment triggering metabolic reprogramming in melanoma cells [Figure 11] with increased pro-
angiogenic VEGF and altered immunosuppression [167] .

Melanocyte-lineage
Microphthalmia-associated transcription factor
The microphthalmia-associated transcription factor (MITF) gene is a key regulator for the development
and differentiation of melanocytes. Melanoma cell phenotype switching is characterized in the ERK/MAP-
kinase pathway [Figure 10] targeting MITF phosphorylation in either transient or sustained activation [177] .