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

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Author

  • 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 B Jönsson
  • Jennifer Landsberg
  • Thomas Tüting
  • Michael Hölzel
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Summary, in English

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.

Department/s

Publishing year

2015

Language

English

Publication/Series

Nature Communications

Volume

6

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Cell and Molecular Biology

Status

Published

Research group

  • Melanoma Genomics

ISBN/ISSN/Other

  • ISSN: 2041-1723