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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

DOI

10.1038/ncomms9755

Type

Journal article

Journal

Nature communications

Publication Date

04/11/2015

Volume

6

Pages

8755 - 8755

Addresses

Unit for RNA Biology, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.

Keywords

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