期刊
GENES & DEVELOPMENT
卷 31, 期 1, 页码 18-33出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.290940.116
关键词
melanoma; phenotype-switching; invasiveness; MITF; TNF alpha
资金
- Ludwig Institute for Cancer Research
- National Institutes of Health [PO1 CA128814-06A1]
- Fundacion Seneca
- Fundacion de la Associacion Espanola Contra el Cancer (FAECC)
- Ministerio de Economia y Competitividad (MINECO)
- Fondo Europeo de Desarrollo Regional [SAF2013-48375-C2-1-R]
- Deutsche Forschungsgemeinschaft [HO4281/2-1]
- Medical Research Council
- Oxford Biomedical Research Centre
- Biotechnology and Biological Sciences Research Council [BB/M006565/1]
- Wellcome Trust [WT098519MA]
- National Cancer Institute [CA128814]
- Cancer Research UK (CRUK through the CRUK Oxford Centre) [C5255/A18085, C5255/A15935]
- Oxford National Institute for Health Research Biomedical Research Centre
- Wellcome Trust [098519/Z/12/Z] Funding Source: Wellcome Trust
- BBSRC [BB/H024980/1, BB/M006565/1] Funding Source: UKRI
- MRC [MC_UP_A600_1023, G0902418] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/H024980/1, BB/M006565/1] Funding Source: researchfish
- Cancer Research UK [23969] Funding Source: researchfish
- Medical Research Council [G0902418, MC_UP_A600_1023] Funding Source: researchfish
- Wellcome Trust [098519/Z/12/Z] Funding Source: researchfish
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.
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