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Published on: May 14, 2016
Genomic hallmarks and therapeutic implications of G0 cell cycle arrest in cancer
Anna J Wiecek1, Stephen J Cutty2, Daniel Kornai1
1UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London, UK.
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.
Insights
Cancer therapy resistance is linked to a dormant G0 cell state. Researchers developed a method to identify this state, revealing its association with specific genomic features and therapeutic unresponsiveness.
Area of Science:
- Oncology
- Genomics
- Cell Biology
Background:
- Therapy resistance in cancer is frequently driven by a subpopulation of cells in a non-proliferative G0 state.
- Identifying and understanding the mutational drivers of this G0 arrested state remains a significant challenge.
Purpose of the Study:
- To develop a robust methodology for identifying the G0 arrested state from transcriptomic data.
- To characterize the prevalence and genomic underpinnings of G0 arrest in solid primary tumors.
- To investigate the link between G0 arrest and therapeutic resistance.
Main Methods:
- Development of a transcriptomic-based methodology to identify G0 arrested cells.
- Genomic analysis of solid primary tumors to determine constraints of G0 arrest.
- Application of machine learning to uncover genomic dependencies and validate gene roles.
- Analysis of single-cell data to assess the impact of G0 arrest on therapy response.
Main Results:
- G0 arrest is associated with more stable, less mutated genomes, intact TP53, and lack of DNA damage repair deficiency.
- Increased APOBEC mutagenesis and novel genomic dependencies for G0 arrest were identified.
- The centrosomal gene CEP89 was validated as a modulator of proliferation and G0 arrest.
- G0 arrest was found to underlie unfavorable responses to cell cycle, kinase signaling, and epigenetic therapies.
Conclusions:
- A G0 arrest transcriptional signature linked to therapeutic resistance was proposed.
- This signature can be utilized for further study and clinical tracking of the G0 state.
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