Biology subjects

Seymour, L.

Publications and source records attributed to Seymour, L..

3 recordsLinked to original sources

bioRxiv2026

The UV potentiated mutational signature of clinical stage G-quadruplex binder CX5461.

Drug-related UVA-induced photoreactions have been reported for several therapeutic compounds, including fluoroquinolones. CX5461 is a clinically relevant quinolone-derived anti-cancer small molecule with documented UVA-sensitising activity. Here we compared, by bulk and clonal whole genome sequencing (WGS) under light-protected conditions, the mutational signatures in human retinal pigment epithelial cells (RPE1) exposed to UVA, CX5461, or co-exposed to UVA and CX5461. Treatment with CX5461 or UVA alone resulted in a low SNV burden and background-like mutational profiles. In contrast, bulk sequencing of human cells co-exposed to UVA and CX5461 had a markedly higher SNV burden characterized by T>A and T>C substitutions. Furthermore, single-cell clonal expansion and sequencing of CX5461 alone, UVA alone or CX5461+UVA treatments confirmed that the pattern was only observed when cells were exposed to both UVA and CX5461. The CX5461+UVA-associated SNV signature we report arises only when CX5461-treated cells are exposed to UVA, and is not observed when CX5461-treated cells are shielded from light. We do not observe strong single base mutagenic activity of CX5461 alone, under light protected conditions. Our data emphasise the need for appropriate controls and light-exposure precautions when studying base mutagenesis activity of known photosensitiser molecules.

cancer biology↗

bioRxiv2025

Machine perfusion and single-cell spatial transcriptome mapping identifies novel immune escape mechanisms in colorectal cancer liver metastasis

Liver metastasis is the terminal stage of colorectal cancer. Immune checkpoint blockade (ICB) has heralded remarkable clinical success across a range of cancer types, but with limited efficacy in replacement-type colorectal liver metastasis (CRLM), the most common and lethal histological subtype. Using a novel human normothermic perfusion model, we demonstrate for the first time, that T-cells preferentially extravasate within the peri-tumoural liver rather than the CRLM. We use single-cell spatial transcriptomics and multiplexed immunofluorescence to validate CRLM T-cell exclusion and show that CRLM endothelia are anergic, lacking key receptors required for T-cell extravasation. CD4 T-cells that extravasate within the peri-tumoural liver are TCR-reactive, yet exhausted, whilst CD4 T-cells within the CRLM demonstrate a stress response, impaired cytokine expression and lack of TCR reactivity. We identify the spatial cellular and molecular interactions underlying these observations, providing novel targets for future attempts to sensitise to immunotherapeutics and a justification for failed ICB efficacy in CRLM.

cancer biology↗

bioRxiv2023

A drug repurposing screen for whipworms informed by comparative genomics

Hundreds of millions of people worldwide are infected with the whipworm Trichuris trichiura. Novel treatments are urgently needed as current drugs, such as albendazole, have relatively low efficacy. We have investigated whether drugs approved for other human diseases could be repurposed as novel anti-whipworm drugs. In a previous comparative genomics analysis, we identified 409 drugs approved for human use that we predicted to target parasitic worm proteins. Here we tested these ex vivo by assessing motility of adult worms of Trichuris muris, the murine whipworm, an established model for human whipworm research. We identified 14 compounds with EC50 values of[≤] 50 M against T. muris ex vivo, and selected nine for testing in vivo. However, the best worm burden reduction seen in mice was just 19%. The high number of ex vivo hits against T. muris shows that we were successful at predicting parasite proteins that could be targeted by approved drugs. In contrast, the low efficacy of these compounds in mice suggest challenges due to their chemical properties (e.g. lipophilicity, polarity, molecular weight) and pharmacokinetics (e.g. absorption, distribution, metabolism, and excretion) that may (i) promote absorption by the host gastrointestinal tract, thereby reducing availability to the worms embedded in the large intestine, and/or (ii) restrict drug uptake by the worms. This indicates that identifying structural analogues that have reduced absorption by the host, and increased uptake by worms, may be necessary for successful drug repurposing against whipworms. Therefore, we recommend that prior to in vivo studies, future researchers first assess drug absorption by the host, for example, using human intestinal organoids or cell lines, and drug uptake by whipworms using intestinal organoids infected with T. muris.

pharmacology and toxicology↗