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Phenotypic plasticity drives cancer progression, impacts treatment response, and is a major driver of therapeutic resistance. In melanoma, a regulatory axis between the MITF and BRN2 transcription factors has been reported to promote tumor heterogeneity by mediating switching between proliferative and invasive phenotypes, respectively. Despite strong evidence that subpopulations of cells that exhibit a BRN2high/MITFlow expression profile switch to a predominantly invasive phenotype, the mechanisms by which this switch is propagated and promotes invasion remain poorly defined. We have found that a reciprocal relationship between BRN2 and NOTCH1/2 signaling exists in melanoma cells in vitro, within patient datasets, and in in vivo primary and metastatic human tumors that bolsters acquisition of invasiveness. Working through the epigenetic modulator EZH2, the BRN2‒NOTCH1/2 axis is potentially a key mechanism by which the invasive phenotype is maintained. Given the emergence of agents targeting both EZH2 and NOTCH, understanding the mechanism through which BRN2 promotes heterogeneity may provide crucial biomarkers to predict treatment response to prevent metastasis.

Original publication




Journal article


The Journal of investigative dermatology

Publication Date





1845 - 1857


School of Biomedical Sciences, at the Translational Research Institute, Queensland University of Technology, Brisbane, Australia; School of Biomedical Sciences, The University of Queensland, Brisbane, Australia; Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA; Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.


Cell Line, Tumor, Humans, Melanoma, Neoplasm Invasiveness, Homeodomain Proteins, Cell Movement, Gene Expression Regulation, Neoplastic, POU Domain Factors, Microphthalmia-Associated Transcription Factor, Receptor, Notch1, Receptor, Notch2