The DOI matches its Crossref record; 18 of the 18 references it cites were found in a registry or an index.
Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma
Open accessAbstract
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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Cited by
De-novo and acquired resistance to immune checkpoint targeting
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Self-citationPhenotype plasticity as enabler of melanoma progression and therapy resistance
Arozarena, I., & Wellbrock, C. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0154-4 · Cited by 381
Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities
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Self-citationIntratumor and Intertumor Heterogeneity in Melanoma
Grzywa, T. M., Paskal, W., & Włodarski, P. K. (2017) · Translational Oncology · doi:10.1016/j.tranon.2017.09.007 · Cited by 299
Metadata
- Authors
- 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.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2017-01-01
- Volume
- 31
- Issue
- 1
- Pages
- 18-33
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W2577256604
- Cited by
- 239
- References
- 18
- Type
- posted content
- Language
- en
- Open access
- diamond
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- 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. (2017). Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma. Genes & Development. https://doi.org/10.1101/gad.290940.116
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
