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

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 i...

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Main Authors:	Riesenberg, Stefanie, Groetchen, Angela, Siddaway, Robert, Bald, Tobias, Reinhardt, Julia, Smorra, Denise, Kohlmeyer, Judith, Renn, Marcel, Phung, Bengt, Aymans, Pia, Schmidt, Tobias, Hornung, Veit, Davidson, Irwin, Goding, Colin R., Jönsson, Göran, Landsberg, Jennifer, Tüting, Thomas, Hölzel, Michael
Format:	Online
Language:	English
Published:	Nature Pub. Group 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659938/

id	pubmed-4659938
recordtype	oai_dc
spelling	pubmed-46599382015-12-04 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 Aymans, Pia Schmidt, Tobias Hornung, Veit Davidson, Irwin Goding, Colin R. Jönsson, Göran Landsberg, Jennifer Tüting, Thomas Hölzel, Michael Article 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. Nature Pub. Group 2015-11-04 /pmc/articles/PMC4659938/ /pubmed/26530832 http://dx.doi.org/10.1038/ncomms9755 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Riesenberg, Stefanie Groetchen, Angela Siddaway, Robert Bald, Tobias Reinhardt, Julia Smorra, Denise Kohlmeyer, Judith Renn, Marcel Phung, Bengt Aymans, Pia Schmidt, Tobias Hornung, Veit Davidson, Irwin Goding, Colin R. Jönsson, Göran Landsberg, Jennifer Tüting, Thomas Hölzel, Michael
spellingShingle	Riesenberg, Stefanie Groetchen, Angela Siddaway, Robert Bald, Tobias Reinhardt, Julia Smorra, Denise Kohlmeyer, Judith Renn, Marcel Phung, Bengt Aymans, Pia Schmidt, Tobias Hornung, Veit Davidson, Irwin Goding, Colin R. Jönsson, Göran Landsberg, Jennifer Tüting, Thomas Hölzel, Michael MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment
author_facet	Riesenberg, Stefanie Groetchen, Angela Siddaway, Robert Bald, Tobias Reinhardt, Julia Smorra, Denise Kohlmeyer, Judith Renn, Marcel Phung, Bengt Aymans, Pia Schmidt, Tobias Hornung, Veit Davidson, Irwin Goding, Colin R. Jönsson, Göran Landsberg, Jennifer Tüting, Thomas Hölzel, Michael
author_sort	Riesenberg, Stefanie
title	MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment
title_short	MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment
title_full	MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment
title_fullStr	MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment
title_full_unstemmed	MITF and c-Jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment
title_sort	mitf and c-jun antagonism interconnects melanoma dedifferentiation with pro-inflammatory cytokine responsiveness and myeloid cell recruitment
description	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.
publisher	Nature Pub. Group
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659938/
_version_	1613506028952879104

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

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