Multiple transcription factors can target a given DNA sequence to control gene expression. Having related transcription factors target the same genes with divergent outcomes could be a mechanism of nongenetic adaptation by which cancer cells accommodate the demands of a changing microenvironment (by, for example, switching from brisk proliferation to differentiation, or simply fleeing the scene). Researchers led by Ludwig Oxford’s Pakavarin Louphrasitthiphol and Colin Goding explored such co-targeting by three closely related transcription factors—TFEB, TFE3 and MITF—in melanoma. They detailed in a December publication in Cell Reports how the three transcription factors influence melanoma progression and cooperate to enable cellular adaptations to the harsh microenvironment of the tumor. Pakavarin, Colin and their colleagues show that far from being redundant, each transcription factor regulates different and often opposing gene expression programs that coordinate differentiation, metabolism and protein synthesis and limit immune cell infiltration of the tumor. MITF, for example, promotes proliferation and glycolysis while TFEB drives differentiation and, along with TFE3, mitochondrial respiration. The regulated exchange of MITF, TFEB and TFE3 enables phenotypic switching that flips cancer cells from proliferation into states conducive to invasion. Significantly, TFE3 suppresses T cell and macrophage immune infiltration into tumors whereas loss of both MITF and TFE3 reverses the effect of loss of TFE3 alone, but instead leads to increased NK cell infiltration.
MITF, TFEB, and TFE3 drive distinct adaptive gene expression programs and immune infiltration in melanoma
Cell Reports, 2025 December 23