title: Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma.
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.
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
authors.forename: Paola
authors.initials: P
authors.lastname: Falletta
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
authors.forename: Luis
authors.initials: L
authors.lastname: Sanchez-Del-Campo
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
authors.forename: Jagat
authors.initials: J
authors.lastname: Chauhan
authors.affiliation: Department of Clinical Chemistry and Clinical Pharmacology, Unit for RNA Biology, University Hospital of Bonn, D-53127 Bonn, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Effern
authors.affiliation: Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom.
authors.forename: Amy
authors.initials: A
authors.lastname: Kenyon
authors.affiliation: 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.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kershaw
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Siddaway
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Lisle
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Freter
authors.affiliation: Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Daniels
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University Hospital Magdeburg, 39120 Magdeburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
authors.affiliation: Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Middleton
authors.affiliation: Department of Oncology, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.affiliation: Medical Research Council Toxicology Unit, Leicester LE1 9HN, United Kingdom.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Willis
authors.affiliation: 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.
authors.forename: Graham
authors.initials: G
authors.lastname: Pavitt
authors.affiliation: Tumour Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Perbys Medical Discovery Institute, La Jolla, California 92037, USA.
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
authors.affiliation: Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Sauka-Spengler
authors.affiliation: Department of Clinical Chemistry and Clinical Pharmacology, Unit for RNA Biology, University Hospital of Bonn, D-53127 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hölzel
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom.
authors.forename: Colin R
authors.initials: CR
authors.lastname: Goding
mesh_terms: D000818:Animals; D000066670:Cell Plasticity / Q000235:genetics*; D060833:Cellular Microenvironment; D065150:Cellular Reprogramming / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D019143:Evolution, Molecular; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D005973:Glutamine / Q000494:pharmacology; D006801:Humans; D007167:Immunotherapy; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009432:Neural Crest / Q000166:cytology; D010641:Phenotype; D014176:Protein Biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; D014157:Transcription Factors; D005973:Glutamine; C101003:ELF2 protein, human
keywords: MITF; TNFα; invasiveness; melanoma; phenotype-switching