MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment

Stefanie Riesenberg, Angela Groetchen, Robert Siddaway, Tobias Bald, Julia Reinhardt, Denise Smorra, Judith Kohlmeyer, Marcel Renn, Bengt Phung, Pia Aymans, Tobias Schmidt, Veit Hornung, Irwin Davidson, Colin R. Goding, Göran Jönsson, Jennifer Landsberg, Thomas Tüting and Michael Hölzel ()
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Stefanie Riesenberg: Unit for RNA Biology, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn
Angela Groetchen: Unit for RNA Biology, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn
Robert Siddaway: Ludwig Institute for Cancer Research, University of Oxford
Tobias Bald: Laboratory for Experimental Dermatology, University Hospital Bonn
Julia Reinhardt: Unit for RNA Biology, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn
Denise Smorra: Unit for RNA Biology, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn
Judith Kohlmeyer: Laboratory for Experimental Dermatology, University Hospital Bonn
Marcel Renn: Laboratory for Experimental Dermatology, University Hospital Bonn
Bengt Phung: Lund University
Pia Aymans: Laboratory for Experimental Dermatology, University Hospital Bonn
Tobias Schmidt: Institute of Molecular Medicine, University Hospital, University of Bonn
Veit Hornung: Institute of Molecular Medicine, University Hospital, University of Bonn
Irwin Davidson: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP
Colin R. Goding: Ludwig Institute for Cancer Research, University of Oxford
Göran Jönsson: Lund University
Jennifer Landsberg: Laboratory for Experimental Dermatology, University Hospital Bonn
Thomas Tüting: Laboratory for Experimental Dermatology, University Hospital Bonn
Michael Hölzel: Unit for RNA Biology, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn

Nature Communications, 2015, vol. 6, issue 1, 1-16

Abstract: Abstract 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 MITFlow/c-Junhigh 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 MITFlow/c-Junhigh melanomas to counteract their growth-promoting and immunosuppressive functions.

Date: 2015
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DOI: 10.1038/ncomms9755

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