The switching of cancer cell phenotypes in response to microenvironmental signals such as low oxygen and low nutrients is increasingly recognised as an important cause of cancer progression and resistance to therapy. In melanoma, the master transcriptional regulator MITF has a key role in phenotype switching and cells with high MITF expression are proliferative and differentiated whereas cells with low MITF expression are invasive, undifferentiated and more resistant to therapy.
Despite previous studies identifying some MITF binding signatures and target genes, these cannot explain the breadth of MITF’s role in melanoma progression and therapy resistance. In this paper published in Pigment Cell and Melanoma Research, Dr Jagat Chauhan from Professor Colin Goding’s laboratory analysed a range of molecular data (genomics, transcriptomics, chromatin immunoprecipitation sequencing and mass spectrometry) obtained from melanoma cell lines and clinical samples so that the role of the microenvironment could be considered.
This study reveals how MITF activity may suppress genes regulated by the transcription factor AP1, a driver of the undifferentiated/invasive phenotype. This may explain MITF’s ability to drive a proliferative/differentiated phenotype and suppress invasion, and demonstrates how understanding MITF’s network could enable prediction of patient survival.
The research also investigated the previously observed relationship between low MITF expression and an increase in tumour immune filtration, for which the mechanism was poorly understood. The authors identified that signalling through the Notch pathway is also associated with immune infiltration in mouse and human melanoma tumours. This has shed light on how immune-rich and immune-poor environments are established within tumours, with potential implications for the success or failure of anti-melanoma immunotherapies.