Wiecek, Anna J;
Cutty, Stephen J;
Kornai, Daniel;
Parreno-Centeno, Mario;
Gourmet, Lucie E;
Tagliazucchi, Guidantonio Malagoli;
Jacobson, Daniel H;
... Secrier, Maria; + view all
(2023)
Genomic hallmarks and therapeutic implications of G0 cell cycle arrest in cancer.
Genome Biology
, 24
(1)
, Article 128. 10.1186/s13059-023-02963-4.
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Abstract
BACKGROUND: Therapy resistance in cancer is often driven by a subpopulation of cells that are temporarily arrested in a non-proliferative G0 state, which is difficult to capture and whose mutational drivers remain largely unknown. RESULTS: We develop methodology to robustly identify this state from transcriptomic signals and characterise its prevalence and genomic constraints in solid primary tumours. We show that G0 arrest preferentially emerges in the context of more stable, less mutated genomes which maintain TP53 integrity and lack the hallmarks of DNA damage repair deficiency, while presenting increased APOBEC mutagenesis. We employ machine learning to uncover novel genomic dependencies of this process and validate the role of the centrosomal gene CEP89 as a modulator of proliferation and G0 arrest capacity. Lastly, we demonstrate that G0 arrest underlies unfavourable responses to various therapies exploiting cell cycle, kinase signalling and epigenetic mechanisms in single-cell data. CONCLUSIONS: We propose a G0 arrest transcriptional signature that is linked with therapeutic resistance and can be used to further study and clinically track this state.
| Type: | Article |
|---|---|
| Title: | Genomic hallmarks and therapeutic implications of G0 cell cycle arrest in cancer |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s13059-023-02963-4 |
| Publisher version: | https://doi.org/10.1186/s13059-023-02963-4 |
| Language: | English |
| Additional information: | © 2023 BioMed Central Ltd. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | Cell cycle arrest, G0, Cancer, Persister cells, Genomic dependencies, Machine learning, Data integration, Bulk/single-cell sequencing |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10170954 |
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