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

Falletta, P., Sanchez-Del-Campo, L., Chauhan, J., Effern, M., Kenyon, A., Kershaw, C.J., Siddaway, R., Lisle, R., Freter, R., Daniels, M.J., Lu, X., Tüting, T., Middleton, M., Buffa, F.M., Willis, A.E., Pavitt, G., Ronai, Z.A., Sauka-Spengler, T., Hölzel, M., Goding, C.R.
Genes & Development   31: 18-33 (Journal)
Registered Authors
Sauka-Spengler, Tatjana
MITF, TNFα, invasiveness, melanoma, phenotype-switching
MeSH Terms
  • Animals
  • Cell Plasticity/genetics*
  • Cellular Microenvironment
  • Cellular Reprogramming/genetics*
  • Drug Resistance, Neoplasm/genetics*
  • Evolution, Molecular
  • Feedback, Physiological
  • Gene Expression Regulation, Neoplastic/drug effects
  • Gene Expression Regulation, Neoplastic/genetics*
  • Glutamine/pharmacology
  • Humans
  • Immunotherapy
  • Melanoma/drug therapy
  • Melanoma/genetics*
  • Melanoma/metabolism
  • Microphthalmia-Associated Transcription Factor/genetics*
  • Neoplasm Invasiveness/genetics
  • Neural Crest/cytology
  • Phenotype
  • Protein Biosynthesis/genetics*
  • Transcription Factors/metabolism
  • Zebrafish/embryology
28096186 Full text @ Genes & Dev.
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes