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Inflammation promotes phenotypic plasticity in melanoma, a source of non-genetic heterogeneity, but the molecular framework is poorly understood. Here we use functional genomic approaches and identify a reciprocal antagonism between the melanocyte lineage transcription factor MITF and c-Jun, which interconnects inflammation-induced dedifferentiation with pro-inflammatory cytokine responsiveness of melanoma cells favouring myeloid cell recruitment. We show that pro-inflammatory cytokines such as TNF-α instigate gradual suppression of MITF expression through c-Jun. MITF itself binds to the c-Jun regulatory genomic region and its reduction increases c-Jun expression that in turn amplifies TNF-stimulated cytokine expression with further MITF suppression. This feed-forward mechanism turns poor peak-like transcriptional responses to TNF-α into progressive and persistent cytokine and chemokine induction. Consistently, inflammatory MITF(low)/c-Jun(high) syngeneic mouse melanomas recruit myeloid immune cells into the tumour microenvironment as recapitulated by their human counterparts. Our study suggests myeloid cell-directed therapies may be useful for MITF(low)/c-Jun(high) melanomas to counteract their growth-promoting and immunosuppressive functions.

Original publication




Journal article


Nat Commun

Publication Date





Animals, Cell Dedifferentiation, Cell Line, Tumor, Chromatin Immunoprecipitation, Cytokines, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Fluorescent Antibody Technique, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, High-Throughput Nucleotide Sequencing, Humans, Immunoblotting, Immunohistochemistry, Inflammation, Melanoma, Mice, Microphthalmia-Associated Transcription Factor, Myeloid Cells, Neoplasm Transplantation, Proto-Oncogene Proteins c-jun, Real-Time Polymerase Chain Reaction, Skin Neoplasms, Tumor Necrosis Factor-alpha