Researchers at the Ludwig Institute for Cancer Research, led by Professor Colin Goding, have uncovered how melanoma cells reprogramme their behaviour to survive stressful environments. The study, published in Cell Reports, provides new insight into melanoma’s remarkable plasticity – the ability of cancer cells to shift identity and function in response to changing conditions.
The researchers show that three closely related transcription factors – MITF, TFEB and TFE3 – previously thought to perform largely overlapping roles, in fact drive distinct gene-expression programmes in melanoma cells. This enables tumour cells to switch between different functional states depending on environmental cues.
A molecular switch for adaptation
MITF is well established as a master regulator of melanoma growth, controlling genes involved in pigmentation and cell proliferation. However, melanoma cells also express TFEB and TFE3, two related transcription factors whose functions have, until now, been less well understood.
Using integrated genomic and transcriptomic analyses, the team found that although all three factors bind many of the same regions of the genome, they activate different sets of genes:
- MITF promotes a proliferative, growth-focused programme.
- TFEB activates lysosomal and autophagy pathways.
- TFE3 drives a programme linked to oxidative metabolism and immune modulation.
Importantly, the balance between these programmes is not fixed. Under conditions of stress – such as nutrient deprivation – melanoma cells reduce MITF activity and shift towards TFEB- and TFE3-driven states. This transition slows proliferation and alters the tumour microenvironment, including immune-cell infiltration.
Taken together, the findings suggest that melanoma cells can use this transcription-factor “dial” to switch between alternative survival strategies. By toggling between distinct transcriptional states, tumour cells can withstand conditions that would otherwise be lethal. This adaptability may help explain why melanoma can persist and recur even after initially successful treatment.
By improving our understanding of how these transcription factors shape melanoma cell behaviour, the study opens up potential new avenues for therapy. In particular, targeting the switch between MITF-driven and TFEB/TFE3-driven programmes could make melanoma cells more vulnerable to treatment.