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

Riesenberg, Stefanie; Groetchen, Angela; Siddaway, Robert; Bald, Tobias; Reinhardt, Julia; Smorra, Denise; Kohlmeyer, Judith; Renn, Marcel; Phung, Bengt LU and Aymans, Pia, et al. (2015) In Nature Communications 6.
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... (More)
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. (Less)
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Nature Communications
volume
6
publisher
Nature Publishing Group
external identifiers
  • pmid:26530832
  • wos:000366298400001
  • scopus:84946569121
ISSN
2041-1723
DOI
10.1038/ncomms9755
language
English
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yes
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1c397a4d-b380-4e07-9cf0-955ae8f38809 (old id 8243394)
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http://www.ncbi.nlm.nih.gov/pubmed/26530832?dopt=Abstract
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2015-12-02 19:04:41
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2017-11-12 03:44:11
@article{1c397a4d-b380-4e07-9cf0-955ae8f38809,
  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.},
  articleno    = {8755},
  author       = {Riesenberg, Stefanie and Groetchen, Angela and Siddaway, Robert and Bald, Tobias and Reinhardt, Julia and Smorra, Denise and Kohlmeyer, Judith and Renn, Marcel and Phung, Bengt and Aymans, Pia and Schmidt, Tobias and Hornung, Veit and Davidson, Irwin and Goding, Colin R and Jönsson, Göran B and Landsberg, Jennifer and Tüting, Thomas and Hölzel, Michael},
  issn         = {2041-1723},
  language     = {eng},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment.},
  url          = {http://dx.doi.org/10.1038/ncomms9755},
  volume       = {6},
  year         = {2015},
}