The role of physics in multiomics and cancer evolution.

Complex interactions between the physical environment and phenotype of a tumour, and genomics, transcriptomics, proteomics and epigenomics, are increasingly known to have a significant influence on cancer development, progression and evolution. For example, mechanical stress can alter both genome maintenance and histone modifications, which consequently affect transcription and the epigenome. Increased stiffness has been linked to genetic heterogeneity and is responsible for heterochromatin accumulations. Stiffness thereby leads to deregulation in gene expression, disrupts the proteome and can impact angiogenesis. Several studies have shown how the physics of cancer can influence diverse cancer hallmarks such as resistance to cell death, angiogenesis and evasion from immune destruction. In this review, we will explain the role that physics of cancer plays in cancer evolution and explore how multiomics are being used to elucidate the mechanisms underpinning them.

Genomic hallmarks and therapeutic implications of G0 cell cycle arrest in cancer.

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.