Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma
| Autor: | Christopher J. Kershaw, Michael Hölzel, Richard Lisle, Ze'ev Ronai, Thomas Tüting, Paola Falletta, Tatjana Sauka-Spengler, Amy Kenyon, Colin R. Goding, Maike Effern, Rasmus Freter, Anne E. Willis, Mark R. Middleton, Robert Siddaway, Xin Lu, Luis Sánchez-del-Campo, Graham D. Pavitt, Jagat Chauhan, Matthew J. Daniels, Francesca M. Buffa |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Senescence Glutamine Cell Plasticity Evolution Molecular 03 medical and health sciences Genetics Animals Humans Integrated stress response Neoplasm Invasiveness Melanoma Transcription factor Zebrafish Feedback Physiological Microphthalmia-Associated Transcription Factor biology ATF4 Cellular Reprogramming Microphthalmia-associated transcription factor 3. Good health Cell biology Gene Expression Regulation Neoplastic Phenotype 030104 developmental biology Cellular Microenvironment Drug Resistance Neoplasm Neural Crest Protein Biosynthesis eIF2B biology.protein Immunotherapy Reprogramming Research Paper Transcription Factors Developmental Biology |
| Zdroj: | Falletta, P, Sanchez-del-Campo, L, Chauhan, J, Effern, M, Kenyon, A, Kershaw, C J, Siddaway, R, Lisle, R J, Freter, R, Daniels, M J, Lu, X, Tüting, T, Middleton, M, Buffa, F M, Willis, A E, Pavitt, G D, Ronai, Z A, Sauka-Spengler, T, Hölzel, M & Goding, C R 2017, ' Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma. ', Genes and development, vol. 31, no. 1, pp. 18-33 . https://doi.org/10.1101/gad.290940.116 |
| ISSN: | 1549-5477 0890-9369 |
| DOI: | 10.1101/gad.290940.116 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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