Abstract
Cells can rapidly adjust their proteomes in dynamic environments by regulating mRNA translation. There is mounting evidence that dysregulation of mRNA translation supports the survival and adaptation of cancer cells, which has stimulated clinical interest in targeting elements of the translation machinery and, in particular, components of the eukaryotic initiation factor 4F (eIF4F) complex such as eIF4E. However, the effect of targeting mRNA translation on infiltrating immune cells and stromal cells in the tumour microenvironment (TME) has, until recently, remained unexplored. In this Perspective article, we discuss how eIF4F-sensitive mRNA translation controls the phenotypes of key non-transformed cells in the TME, with an emphasis on the underlying therapeutic implications of targeting eIF4F in cancer. As eIF4F-targeting agents are in clinical trials, we propose that a broader understanding of their effect on gene expression in the TME will reveal unappreciated therapeutic vulnerabilities that could be used to improve the efficacy of existing cancer therapies.
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Acknowledgements
The authors apologize to authors whose work we have not cited owing to the focus of this Perspective article and space constraints. The authors are grateful to G. Ursini-Siegel for critical reading of this manuscript. M.B. is supported by the International Postdoc Grant from the Swedish Research Council (VR). M.J.A. is sponsored by a Quebec Research Fund (FRQS) doctorate fellowship. Work in the S.V.D.R. Laboratory is funded by the Canadian Institutes of Health Research (grant PJT-162260) and by the Canadian Cancer Society (grant 707140). The research team of C.R. is supported by grants from Swedish Cancer Association (CAN 2019/028), Swedish Research Council (VR 2021-02915), the Stockholm Cancer society and the Childhood Cancer Foundation; the laboratory of O.L. is supported by grants from the Swedish Research Council (2020-01665), the Swedish Cancer Society (19 0314), the Stockholm Cancer Society and the Wallenberg Academy Fellow’s programme.
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All authors contributed substantially to discussion of the content and reviewed/edited the manuscript before submission. S.V.d.R., M.B., M.J.A., O.L. and C.R. researched data for the article and wrote the article.
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Glossary
- G-quadruplexes
-
A type of secondary structure that can be adopted by nucleic acid sequences.
- Puromycin incorporation
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A method that quantifies the global level of protein synthesis.
- Rocaglates
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A family of compounds that perturb the activity of the eIF4F subunit eIF4A through a gain-of-function mechanism.
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Bartish, M., Abraham, M.J., Gonçalves, C. et al. The role of eIF4F-driven mRNA translation in regulating the tumour microenvironment. Nat Rev Cancer 23, 408–425 (2023). https://doi.org/10.1038/s41568-023-00567-5
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DOI: https://doi.org/10.1038/s41568-023-00567-5
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