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The plasticity of mRNA translation during cancer progression and therapy resistance

Abstract

Translational control of mRNAs during gene expression allows cells to promptly and dynamically adapt to a variety of stimuli, including in neoplasia in response to aberrant oncogenic signalling (for example, PI3K–AKT–mTOR, RAS–MAPK and MYC) and microenvironmental stress such as low oxygen and nutrient supply. Such translational rewiring allows rapid, specific changes in the cell proteome that shape specific cancer phenotypes to promote cancer onset, progression and resistance to anticancer therapies. In this Review, we illustrate the plasticity of mRNA translation. We first highlight the diverse mechanisms by which it is regulated, including by translation factors (for example, eukaryotic initiation factor 4F (eIF4F) and eIF2), RNA-binding proteins, tRNAs and ribosomal RNAs that are modulated in response to aberrant intracellular pathways or microenvironmental stress. We then describe how translational control can influence tumour behaviour by impacting on the phenotypic plasticity of cancer cells as well as on components of the tumour microenvironment. Finally, we highlight the role of mRNA translation in the cellular response to anticancer therapies and its promise as a key therapeutic target.

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Fig. 1: The process of mRNA translation.
Fig. 2: Plasticity of translational control.
Fig. 3: Oncogenic signalling activates eIF4F.
Fig. 4: Stress-induced shutdown of translation.
Fig. 5: Translational control of cancer cell plasticity.
Fig. 6: Translational control of cancer cell immune evasion.
Fig. 7: Translational control of resistance to anticancer drugs.

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Acknowledgements

The authors thank Institut Curie, CNRS, INSERM and Ligue Nationale Contre le Cancer Equipe Labellisée for funding. L.F. was funded by a postdoctoral fellowship from Fondation ARC.

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L.F. and A.C. researched data for the article. All authors contributed substantially to discussion of the content. L.F., A.C. and S.V. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Stéphan Vagner.

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Competing interests

C.R. is an occasional consultant for Bristol Myers Squibb, MSD, Novartis, Sanofi, AstraZeneca, Pfizer, Roche and Pierre Fabre. C.R. and S.V. are scientific founders of Aglaia Therapeutics. L.F. and A.C. declare no competing interests.

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Nature Reviews Cancer thanks F. Gebauer, K. De Keersmaecker and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

RNA-binding proteins

(RBPs). Proteins that bind single-stranded or double-stranded RNA through specific structural motifs to regulate RNA metabolism and function. Some proteins capable of binding RNA lack conventional RNA-binding domains.

Codon usage

The frequency with which synonymous codons (different codons that encode the same amino acid) occur within a genome.

Upstream open reading frames

(uORFs). Cis-acting elements within the 5′ leader sequence of transcripts with an initiation codon in frame with a termination codon that differs from that associated with the main ORF.

40S ribosomal subunit

Smaller subunit of eukaryotic ribosomes (also known as 80S ribosomes) consisting of 33 proteins and an 18S rRNA. It binds initiation factors that facilitate scanning of mRNAs and the initiation of protein synthesis.

Internal ribosome entry site (IRES) elements

Cis-acting regions on transcripts that promote the cap-independent, internal initiation of translation. IRES elements are classified on the basis of conserved RNA motifs that impact RNA–protein interactions to drive IRES-mediated translation.

Kozak sequence

Optimal mRNA sequence surrounding the AUG start codon and defined as 5′-(A/G)CCAUGG-3′.

N 6-Methyladenosine (m6A) methylation

The reversible methylation of adenine at the sixth position (N-methyladenosine) on RNAs that contributes to the post-transcriptional regulation of gene expression in development and in disease.

Synonymous codons

Different codons (nucleotide triplet combinations) mediating the insertion of the same amino acid into a polypeptide chain.

U34 wobble position

Uridines at position 34 (U34) (also known as the wobble position) located in the anticodon loop of tRNA that can contain modifications allowing more flexible and non-Watson–Crick codon–anticodon base pairing.

Programmed −1 ribosomal frameshifting

Controlled slippage of the translating ribosome that shifts the reading frame by one base in the 5′ direction during translation.

Integrated stress response

(ISR). A cellular pathway induced by various stresses that cause one of the four eukaryotic initiation factor 2α (eIF2α) kinases to phosphorylate eIF2, leading to a global decrease in protein synthesis but the induction of specific genes that promote the restoration of cellular homeostasis.

Stress granules

Stress induced, membraneless assemblies of non-translating messenger ribonucleoproteins in the cytoplasm that sequester specific mRNAs stalled in translation in response to stress.

tRNA fragmentation

Cleavage of tRNA to produce tRNA-derived fragments. The stress-induced cleavage of some tRNAs at the anticodon loop produces tRNA fragments that globally inhibit translation elongation.

Small nucleolar RNAs

(snoRNAs). Metabolically stable, 60–300-nucleotide-long RNAs abundant in the nucleolus and involved in the post-transcriptional modification (2′-O-ribose methylation or pseudouridylation) of ribosomal RNAs and other cellular RNAs.

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Fabbri, L., Chakraborty, A., Robert, C. et al. The plasticity of mRNA translation during cancer progression and therapy resistance. Nat Rev Cancer 21, 558–577 (2021). https://doi.org/10.1038/s41568-021-00380-y

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