Biology subjects

Trevers, K.

Publications and source records attributed to Trevers, K..

3 recordsLinked to original sources

bioRxiv2026

Epithelial Stem Cell Fate Determines Chemoradiotherapy Response in Rectal Cancer

Rectal cancers are often treated with neoadjuvant chemoradiotherapy (CRT), yet 85% of patients do not achieve a pathological complete response. To identify the molecular determinants of CRT response, we profiled the single-cell signalling, DNA-damage, cell-cycle, apoptotic, and cell-fate responses of 2,769 patient-derived organoid cultures treated with CRT, cancer-associated fibroblasts (CAFs), and signal-rewiring agents. We find that CRT response is determined by stem cell-fate. CRT triggers comparable DNA-damage in isogenic proliferative (proCSC) and revival (revCSC) colonic stem cells, but proCSC retain damage and die whereas revCSC resolve damage and persist. Both CRT and CAFs drive proCSC to a common treatment-resistant revCSC fate and high revCSC predicts worse survival in patients. Pharmacologically constraining stem-cell plasticity increases CRT sensitivity, and Spatial Perturbation of ARrayed Tumour Assembloids (SPARTA) confirms YAP/TEAD inhibition improves chemotherapy responses in human stromal-tumour models. These results suggest that cancer cell-fate, not genotoxic damage itself, ultimately governs response to standard-of-care chemoradiotherapy. HIGHLIGHTSO_LIRectal cancer stem cell-fate determines chemoradiotherapy-induced apoptosis C_LIO_LIproCSCs retain DNA-damage and die, whereas revCSCs repair damage and persist C_LIO_LICAFs and chemoradiotherapy converge on a common chemo-radioresistant revCSC state C_LIO_LISPARTA reveals TEAD inhibition blocks DNA-repair persisters in stromal assembloids C_LI

cancer biology↗

bioRxiv2024

SAVANA: reliable analysis of somatic structural variants and copy number aberrations in clinical samples using long-read sequencing

Accurate detection of somatic structural variants (SVs) and copy number aberrations (SCNAs) is critical to inform the diagnosis and treatment of human cancers. Here, we describe SAVANA, a computationally efficient algorithm designed for the joint analysis of somatic SVs, SCNAs, tumour purity and ploidy using long-read sequencing data. SAVANA relies on machine learning to distinguish true somatic SVs from artefacts and provide prediction errors for individual SVs. Using high-depth Illumina and nanopore whole-genome sequencing data for 99 human tumours and matched normal samples, we establish best practices for benchmarking SV detection algorithms across the entire genome in an unbiased and data-driven manner using simulated and sequencing replicates of tumour and matched normal samples. SAVANA shows significantly higher sensitivity, and 9- and 59-times higher specificity than the second and third-best performing algorithms, yielding orders of magnitude fewer false positives in comparison to existing long-read sequencing tools across various clonality levels, genomic regions, SV types and SV sizes. In addition, SAVANA harnesses long-range phasing information to detect somatic SVs and SCNAs at single-haplotype resolution. SVs reported by SAVANA are highly consistent with those detected using short-read sequencing, including complex events causing oncogene amplification and tumour suppressor gene inactivation. In summary, SAVANA enables the application of long-read sequencing to detect SVs and SCNAs reliably in clinical samples.

cancer biology↗

bioRxiv2023

Mechanisms underpinning osteosarcoma genome complexity and evolution

Osteosarcoma is the most common primary cancer of bone with a peak incidence in children and young adults. Despite progress, the genomic aberrations underpinning osteosarcoma evolution remain poorly understood. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of tumours. Chromothripsis drives the acquisition of oncogenic mutations and generates highly unstable derivative chromosomes, the evolution of which drives clonal diversification and intra-tumour heterogeneity. In addition, we report a novel mechanism, loss-translocation-amplification (LTA) chromothripsis, which mediates rapid malignant transformation and punctuated evolution in about half of paediatric and adult high-grade osteosarcomas. Specifically, a single double-strand break triggers concomitant TP53 inactivation and segmental amplifications, often amplifying oncogenes to high copy numbers in extrachromosomal circular DNA elements through breakage-fusion-bridge cycles involving multiple chromosomes. LTA chromothripsis is detected at low frequency in soft-tissue sarcomas, but not in epithelial cancers, including those driven by TP53 mutation. Finally, we identify genome-wide loss of heterozygosity as a strong prognostic indicator for high-grade osteosarcoma.

cancer biology↗