Format

Send to

Choose Destination
Genes Dev. 2017 Jan 1;31(1):18-33. doi: 10.1101/gad.290940.116. Epub 2017 Jan 17.

Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma.

Author information

1
Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
2
Department of Clinical Chemistry and Clinical Pharmacology, Unit for RNA Biology, University Hospital of Bonn, D-53127 Bonn, Germany.
3
Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom.
4
Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, Manchester M13 9PT, United Kingdom.
5
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
6
Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University Hospital Magdeburg, 39120 Magdeburg, Germany.
7
Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
8
Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom.
9
Tumour Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Perbys Medical Discovery Institute, La Jolla, California 92037, USA.

Abstract

The intratumor microenvironment generates phenotypically distinct but interconvertible malignant cell subpopulations that fuel metastatic spread and therapeutic resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage survival oncogene microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence, and drug resistance. However, how MITF is suppressed in vivo and how MITF-low cells in tumors escape senescence are poorly understood. Here we show that microenvironmental cues, including inflammation-mediated resistance to adoptive T-cell immunotherapy, transcriptionally repress MITF via ATF4 in response to inhibition of translation initiation factor eIF2B. ATF4, a key transcription mediator of the integrated stress response, also activates AXL and suppresses senescence to impose the MITF-low/AXL-high drug-resistant phenotype observed in human tumors. However, unexpectedly, without translation reprogramming an ATF4-high/MITF-low state is insufficient to drive invasion. Importantly, translation reprogramming dramatically enhances tumorigenesis and is linked to a previously unexplained gene expression program associated with anti-PD-1 immunotherapy resistance. Since we show that inhibition of eIF2B also drives neural crest migration and yeast invasiveness, our results suggest that translation reprogramming, an evolutionarily conserved starvation response, has been hijacked by microenvironmental stress signals in melanoma to drive phenotypic plasticity and invasion and determine therapeutic outcome.

KEYWORDS:

MITF; TNFα; invasiveness; melanoma; phenotype-switching

PMID:
28096186
PMCID:
PMC5287109
DOI:
10.1101/gad.290940.116
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center