title: MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment.
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 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.
authors.affiliation: Unit for RNA Biology, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Riesenberg
authors.affiliation: Unit for RNA Biology, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Groetchen
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Headington, Oxford OX3 7DQ, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Siddaway
authors.affiliation: Laboratory for Experimental Dermatology, Department of Dermatology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bald
authors.affiliation: Unit for RNA Biology, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Reinhardt
authors.affiliation: Unit for RNA Biology, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Smorra
authors.affiliation: Laboratory for Experimental Dermatology, Department of Dermatology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Kohlmeyer
authors.affiliation: Laboratory for Experimental Dermatology, Department of Dermatology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Renn
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Barngatan 2B, Lund 221 85, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Phung
authors.affiliation: Laboratory for Experimental Dermatology, Department of Dermatology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Pia
authors.initials: P
authors.lastname: Aymans
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Institute of Molecular Medicine, University Hospital, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, Illkirch Cédex 67404, France.
authors.forename: Irwin
authors.initials: I
authors.lastname: Davidson
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Headington, Oxford OX3 7DQ, UK.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Goding
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Barngatan 2B, Lund 221 85, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
authors.affiliation: Laboratory for Experimental Dermatology, Department of Dermatology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Landsberg
authors.affiliation: Laboratory for Experimental Dermatology, Department of Dermatology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
authors.affiliation: Unit for RNA Biology, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hölzel
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation / Q000235:genetics* / Q000276:immunology; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007249:Inflammation; D008545:Melanoma / Q000235:genetics* / Q000276:immunology; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology*; D009368:Neoplasm Transplantation; D016755:Proto-Oncogene Proteins c-jun; D060888:Real-Time Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D016207:Cytokines; D051739:Microphthalmia-Associated Transcription Factor; D016755:Proto-Oncogene Proteins c-jun; D014409:Tumor Necrosis Factor-alpha