Biology subjects

Grant, H.

Publications and source records attributed to Grant, H..

5 recordsLinked to original sources

bioRxiv2026

Spatiotemporal profiling of T cell repertoires in Lynch syndrome reveals convergent immune responses through neoplastic progression

Surveillance of individuals with Lynch syndrome (LS), who are carriers of heterozygous inactivating mismatch repair (MMR) gene mutations that predispose to colorectal cancer, enables the study of tumour-immune coevolution during tumour initiation. Somatic loss of MMR activity in the LS colon leads to the accrual of cancer driver mutations, and also of neoantigens likely to generate an adaptive immune response. However, the spatial and temporal immune dynamics in colon and peripheral blood are uncharacterised. Here we show that the neoplastic evolution of mismatch repair deficient (MMRd) clones leads to large-scale and sustained reorganisation of the T-cell repertoire in colon and peripheral blood. We performed dense spatiotemporal profiling of T cell receptor (TCR) repertoires from 109 colonic biopsies (11 tumour samples, 98 normal bowel) from seven individuals, with eight matched blood repertoires. We additionally analysed 13 colorectal polyp repertoires from eight participants, 286 cross sectional blood repertoires from 242 participants (198 LS and 44 non-LS) and 52 longitudinal peripheral blood samples from 26 individuals with LS. We detected tumour-associated T cell clones, some of which were widely present in normal bowel tissue and also detectable in peripheral blood. Sequence similarity analysis revealed conserved TCR architectures across tissue compartments and recurrent clustering patterns between patients, that were not present in non-Lynch controls, consistent with convergent MMRd-associated antigen-driven immune selection. We identified systemic signatures associated with local tumour immune activity and revealed evidence of structured repertoire remodelling before overt malignancy. Longitudinal profiling revealed frequent turnover of low-abundance clonotypes, whereas highly abundant clonotypes persisted for several years. Collectively, our data defines the local and circulating TCR landscape associated with colonic neoplasia in LS, and provides a framework for LS blood-based immune monitoring, early interception and biomarker development.

immunology↗

bioRxiv2026

The 3D Ultrastructure of C. elegans Gut Granules

We identify an endoderm-restricted organelle in published volume electron microscopy datasets of C. elegans embryos. The organelle consists of a tubular ring surrounding a membrane-bound compartment harboring a prominent dense particle and exhibits a basal polarity and size concordant with canonical gut granules. This finding offers ultrastructural detail to recent evidence that gut granules are bi-lobed organelles with two distinct compartments.

cell biology↗

bioRxiv2025

Single cell multi-omic whole genome sequencing and chromatin accessibility profiling reveals genome-epigenome coevolution in colorectal cancer

Epigenetic alterations co-evolve with genetic mutations to drive carcinogenesis and treatment response. Resolving genome-epigenome coevolution requires accurate multi-omic single cell measurement. Here we develop a new technology called "double ATAC" (dATAC) for high-throughput, high-quality, concurrent whole genome sequencing and chromatin accessibility profiling of individual somatic cells. dATAC is a "one pot" method that uses two rounds of tagmentation to sequentially label open chromatin regions and then the whole genome, and produces data of the same quality as current leading single-omic methods. Using colorectal cancer as a model system, we apply dATAC to reveal convergent reorganisation of the epigenome across expanding drug-resistant clones during 5-FU chemotherapy exposure, remarkable stoichiometry of chromatin accessibility at somatic copy number alterations, and the clonal expansion of copy-number altered T cells in the stroma of metastatic disease. dATAC is a robust single cell technology to accurately profile genome-epigenome coevolution across tissues, diseases and species.

molecular biology↗

bioRxiv2024

Long deletion signatures in repetitive genomic regions track somatic evolution and enable sensitive detection of microsatellite instability

Deficiency in the mismatch repair system (MMRd) causes microsatellite instability (MSI) in cancers and determines eligibility for immunotherapy. Here, we show that MMRd tumours harbour long-deletion signatures ([≥]2-5+ base pairs deleted in repetitive regions), which provide new insights into MSI evolution and enable sensitive MSI detection particularly in challenging clinical samples. Long deletions, accumulated through stepwise DNA slippage errors, are significantly more prevalent in metastatic MMRd tumours compared to primary tumours. Importantly, we show that long-deletion signatures harbour features that are distinct from background noise, making them robustly detectable even in shallow whole genome sequencing (sWGS, [~]0.1X coverage) of formalin-fixed samples. We constructed a machine learning classifier that uses these distinct features to detect Microsatellite Instability in LOw-quality (MILO) samples. MILO achieved 100% accuracy in detecting MSI in sWGS data with only 2%-15% tumour purity and demonstrated promise in identifying MMRd clones in precancerous intestinal lesions. We propose that MILO could be clinically used for the sensitive monitoring of MMRd cancer evolution from early to late stages, using minimal sequencing data from both archival and fresh-frozen samples with low tumour content. SignificanceMutational signatures characterised by long deletions in repetitive genomic regions provide a sensitive route to detect and track MMRd clone evolution, even with low purity shallow whole genome sequencing data.

bioinformatics↗

bioRxiv2020

Larger organ size caused by obesity is a mechanism for higher cancer risk.

Obesity increases significantly cancer risk in various organs. Although this has been recognized for decades, the mechanism through which this happens has never been explained. Here, we show that obese people (BMI [≥]30) have on average 55% (95%CI: 46%-66%), 68% (95%CI: 59%-76%), and 39% (95%CI: 29%-49%) larger kidneys, liver, and pancreas, respectively. We also find a significant linear relationship between the increase in organ volume and the increase in cancer risk (P-value<10-12). These results provide a mechanism explaining why obese individuals have higher cancer risk in several organs: the larger the organ volume the more cells at risk of becoming cancerous. These findings are important for a better understanding of the effects that obesity has on cancer risk and, more generally, for the development of better preventive strategies to limit the mortality caused by obesity.

cancer biology↗