The Role of EIF4F-driven MRNA Translation in Regulating the Tumour Microenvironment

Overview

Journal Nat Rev Cancer

Specialty Oncology

Date 2023 May 4

PMID 37142795

Authors

Margarita Bartish

Madelyn J Abraham

Christophe Goncalves

Ola Larsson

Charlotte Rolny

Sonia V del Rincon

Affiliations

Soon will be listed here.

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.

Citing Articles

Recent advances in the bench-to-bedside translation of cancer nanomedicines.

Liu Y, Zhang Y, Li H, Hu T Acta Pharm Sin B. 2025; 15(1):97-122.

PMID: 40041906 PMC: 11873642. DOI: 10.1016/j.apsb.2024.12.007.

eIF4F-mediated dysregulation of mRNA translation in cancer.

Amiri M, Mahmood N, Tahmasebi S, Sonenberg N RNA. 2025; 31(3):416-428.

PMID: 39809544 PMC: 11874970. DOI: 10.1261/rna.080340.124.

tsRNA in head and neck tumors: Opportunities and challenges in the field.

Wu Z, Xu Y, Zhou C, Zhang Y, Chen J Noncoding RNA Res. 2024; 10:223-230.

PMID: 39468996 PMC: 11513501. DOI: 10.1016/j.ncrna.2024.10.003.

Reciprocal Dynamics of Metabolism and mRNA Translation in Tumor Angiogenesis.

Lidonnici J, Oberkersch R Int J Mol Sci. 2024; 25(20).

PMID: 39457064 PMC: 11508371. DOI: 10.3390/ijms252011284.

Reprograming immunosuppressive microenvironment by eIF4G1 targeting to eradicate pancreatic ductal adenocarcinoma.

He L, Zhang X, Shi F, Zhang H, Chen Y, Sun K Cell Rep Med. 2024; 5(10):101731.

PMID: 39303711 PMC: 11513812. DOI: 10.1016/j.xcrm.2024.101731.

References

Wang Z, Gerstein M, Snyder M . RNA-Seq: a revolutionary tool for transcriptomics. Nat Rev Genet. 2008; 10(1):57-63. PMC: 2949280. DOI: 10.1038/nrg2484. View

Aebersold R, Mann M . Mass-spectrometric exploration of proteome structure and function. Nature. 2016; 537(7620):347-55. DOI: 10.1038/nature19949. View

Schwanhausser B, Busse D, Li N, Dittmar G, Schuchhardt J, Wolf J . Global quantification of mammalian gene expression control. Nature. 2011; 473(7347):337-42. DOI: 10.1038/nature10098. View

Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z . Proteogenomic characterization of human colon and rectal cancer. Nature. 2014; 513(7518):382-7. PMC: 4249766. DOI: 10.1038/nature13438. View

Mun D, Bhin J, Kim S, Kim H, Jung J, Jung Y . Proteogenomic Characterization of Human Early-Onset Gastric Cancer. Cancer Cell. 2019; 35(1):111-124.e10. DOI: 10.1016/j.ccell.2018.12.003. View

Tang W, Zhou M, Dorsey T, Prieto D, Wang X, Ruppin E . Integrated proteotranscriptomics of breast cancer reveals globally increased protein-mRNA concordance associated with subtypes and survival. Genome Med. 2018; 10(1):94. PMC: 6276229. DOI: 10.1186/s13073-018-0602-x. View

Bartish M, Tong D, Pan Y, Wallerius M, Liu H, Ristau J . MNK2 governs the macrophage antiinflammatory phenotype. Proc Natl Acad Sci U S A. 2020; 117(44):27556-27565. PMC: 7959504. DOI: 10.1073/pnas.1920377117. View

Fabbri L, Chakraborty A, Robert C, Vagner S . The plasticity of mRNA translation during cancer progression and therapy resistance. Nat Rev Cancer. 2021; 21(9):558-577. DOI: 10.1038/s41568-021-00380-y. View

Bhat M, Robichaud N, Hulea L, Sonenberg N, Pelletier J, Topisirovic I . Targeting the translation machinery in cancer. Nat Rev Drug Discov. 2015; 14(4):261-78. DOI: 10.1038/nrd4505. View

10.

Hanahan D, Coussens L . Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012; 21(3):309-22. DOI: 10.1016/j.ccr.2012.02.022. View

11.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

12.

ODonnell J, Teng M, Smyth M . Cancer immunoediting and resistance to T cell-based immunotherapy. Nat Rev Clin Oncol. 2018; 16(3):151-167. DOI: 10.1038/s41571-018-0142-8. View

13.

Robert C . A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun. 2020; 11(1):3801. PMC: 7393098. DOI: 10.1038/s41467-020-17670-y. View

14.

Ribas A, Wolchok J . Cancer immunotherapy using checkpoint blockade. Science. 2018; 359(6382):1350-1355. PMC: 7391259. DOI: 10.1126/science.aar4060. View

15.

Su S, Zhao J, Xing Y, Zhang X, Liu J, Ouyang Q . Immune Checkpoint Inhibition Overcomes ADCP-Induced Immunosuppression by Macrophages. Cell. 2018; 175(2):442-457.e23. DOI: 10.1016/j.cell.2018.09.007. View

16.

Binnewies M, Roberts E, Kersten K, Chan V, Fearon D, Merad M . Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018; 24(5):541-550. PMC: 5998822. DOI: 10.1038/s41591-018-0014-x. View

17.

Mariathasan S, Turley S, Nickles D, Castiglioni A, Yuen K, Wang Y . TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018; 554(7693):544-548. PMC: 6028240. DOI: 10.1038/nature25501. View

18.

Tang T, Huang X, Zhang G, Hong Z, Bai X, Liang T . Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy. Signal Transduct Target Ther. 2021; 6(1):72. PMC: 7896069. DOI: 10.1038/s41392-020-00449-4. View

19.

Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C . HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell. 2011; 19(1):31-44. DOI: 10.1016/j.ccr.2010.11.009. View

20.

de Palma M, Biziato D, Petrova T . Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017; 17(8):457-474. DOI: 10.1038/nrc.2017.51. View