Genomic hallmarks of cellular dormancy in cancer and therapeutic implications
Wiecek, A. J.; Cutty, S. J.; Kornai, D.; Parreno-Centeno, M.; Gourmet, L. E.; Malagoli Tagliazucchi, G.; Jacobson, D. H.; Zhang, P.; Xiong, L.; Bond, G. L.; Barr, A. R.; Secrier, M.
Show abstract
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. We developed methodology to robustly identify this state from transcriptomic signals and characterised 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/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, and propose a G0 arrest transcriptional signature that is linked with therapeutic resistance and can be used to further study and clinically track this state.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Time-, tissue- and treatment-associated heterogeneity in tumour-residing migratory DCs 97%
- Integration of scHi-C and scRNA-seq data defines distinct 3D-regulated and biological-context dependent cell subpopulations 97%
- An improved epigenetic counter to track mitotic age in normal and precancerous tissues 97%
Similar papers in this journal
- APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer 97%
- Functional interrogation uncovers a critical role for a high-plasticity cell state in lung adenocarcinoma 97%
- ecDNA amplification of MYC drives intratumor copy-number heterogeneity and adaptation to stress in PDAC 97%
Similar papers in this journal
- Cell cycle alterations associate with a redistribution of mutation rates across chromosomal domains in human cancers 97%
- Differential chromatin accessibility and transcriptional dynamics define breast cancer subtypes and their lineages 97%
- Multi-modal digital pathology for colorectal cancer diagnosis by high-plex immunofluorescence imaging and traditional histology of the same tissue section 96%
Similar papers in this journal
- Increased RNA and protein degradation is required for counteracting transcriptional burden and proteotoxic stress in human aneuploid cells 96%
- Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma 96%
- Precision combination therapies based on recurrent oncogenic co-alterations 96%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.