A5035431621- Glioma Diagnosis and Treatment
- Single-cell and spatial transcriptomics
- Cancer Genomics and Diagnostics
- Ferroptosis and cancer prognosis
- RNA modifications and cancer
- RNA Research and Splicing
- Cancer-related molecular mechanisms research
- MicroRNA in disease regulation
- Cancer Research and Treatments
- Electrochemical Analysis and Applications
- Genetic factors in colorectal cancer
- Colorectal Cancer Treatments and Studies
- Advanced biosensing and bioanalysis techniques
- Pancreatic and Hepatic Oncology Research
- Colorectal Cancer Surgical Treatments
- Immune cells in cancer
- Mathematical Biology Tumor Growth
- Nanoplatforms for cancer theranostics
- Bioinformatics and Genomic Networks
- Genomics and Phylogenetic Studies
- Analytical Chemistry and Sensors
- Molecular Biology Techniques and Applications
- Epigenetics and DNA Methylation
University of Leeds
2017-2025
St James's University Hospital
2019-2025
Wellcome Trust
2020
Patient-based cancer models are essential tools for studying tumor biology and the assessment of drug responses in a translational context. We report establishment large cohort unique organoids patient-derived orthotopic xenografts (PDOX) various glioma subtypes, including gliomas with mutations IDH1, paired longitudinal PDOX from primary recurrent tumors same patient. show that PDOXs enable long-term propagation patient represent clinically relevant avatars retain histopathological,...
Glioblastoma (GBM) brain tumors lacking IDH1 mutations (IDHwt) have the worst prognosis of all neoplasms. Patients receive surgery and chemoradiotherapy but almost always fatally recur.
Single-cell RNA sequencing has revolutionized our understanding of cellular heterogeneity, but routine methods require cell lysis and fail to probe the dynamic trajectories responsible for state transitions, which can only be inferred. Here, we present a nanobiopsy platform that enables injection exogenous molecules multigenerational longitudinal cytoplasmic sampling from single its progeny. The technique is based on scanning ion conductance microscopy (SICM) and, as proof concept, was...
Glioblastoma (GBM) presents a significant clinical challenge due to its aggressive nature and extensive heterogeneity. Tumour purity, the proportion of malignant cells within tumour, is an important covariate for understanding disease, having direct relevance or obscuring signal portion in molecular analyses bulk samples. However, current methods estimating tumour purity are non-specific technically demanding. Therefore, we aimed build reliable accessible estimator GBM. We developed...
Abstract Intratumour heterogeneity provides tumours with the ability to adapt and acquire treatment resistance. The development of more effective personalised treatments for cancers, therefore, requires accurate characterisation clonal architecture tumours, enabling evolutionary dynamics be tracked. Many methods exist achieving this from bulk tumour sequencing data, involving identifying mutations performing subclonal deconvolution, but there is a lack systematic benchmarking inform...
Many traits of cancer progression (e.g., development metastases or resistance to therapy) are facilitated by tumour evolution: Darwinian selection subclones with distinct genotypes phenotypes that enable such progression. Characterising these provide an opportunity develop drugs better target their specific properties but requires the accurate identification somatic mutations shared across multiple spatiotemporal tumours from same patient. Current best practices for calling optimised single...
Abstract Treatment options for adult patients with glioma has remained largely unchanged over the past three decades. Targeted inhibitors and immunotherapies have improved outcomes many cancer types but their relevance in is unclear. The inevitability of disease recurrence demands an understanding mechanisms driving therapy resistance. Glioma Longitudinal Analysis (GLASS) Consortium was initiated to establish a definitive portrait process discover vulnerabilities that render tumor sensitive...
Genomic technologies are increasingly used clinically for both diagnosis and guiding cancer therapy. However, formalin fixation can compromise DNA quality. This study aimed to optimise tissue using normal colon, liver uterus (n=8 each) by varying neutral buffered (NBF) concentration (1%-5% w/v) time (24-48 hours). Fixation 4% NBF improved quality (assessed qPCR) compared with routine (4% unbuffered formal saline-fixed) specimens (p<0.01). Further improvements were achieved reducing...
Tumour evolution results in progressive cancer phenotypes such as metastatic spread and treatment resistance. To better treat cancers, we must characterize tumour the genetic events that confer phenotypes. This is facilitated by high coverage genome or exome sequencing. However, best approach which, indeed whether, these data can be used to accurately model interpret underlying evolutionary dynamics yet confirmed. Establishing this requires sequencing from appropriately heterogeneous tumours...
Abstract Background Glioblastoma (GBM) presents a significant clinical challenge due to its aggressive nature and extensive heterogeneity. Tumour purity, the proportion of malignant cells within tumour, is an important covariate for understanding disease, having direct relevance or obscuring signal portion in molecular analyses bulk samples. However, current methods estimating tumour purity are non-specific, unreliable technically demanding. Therefore, we aimed build reliable accessible...
ABSTRACT Single-cell RNA sequencing has revolutionised our understanding of cellular heterogeneity, but whether using isolated cells or more recent spatial transcriptomics approaches, these methods require isolation and lysis the cell under investigation. This provides a snapshot transcriptome from which dynamic trajectories, such as those that trigger state transitions, can only be inferred. Here, we present nanobiopsy: platform enables simultaneous labelling sampling single without killing...
ABSTRACT Background Glioblastoma (GBM) is a fatal and incurable brain cancer with dismal prognosis. In order to impact on this disease, we need understand how infiltrating, non resectable tumour cells resist chemoradiation facilitate disease recurrence. To end, generated or acquired bulk RNA sequencing data from 45 paired primary locally recurrent GBM tumours (split into original validation cohorts) patients that received standard treatment. We also DNA methylation profiles for 9 pairs...
Abstract Glioblastoma (GBM) brain tumours lacking IDH1 mutations (IDHwt) have the worst prognosis of all neoplasms. Patients receive surgery and chemoradiotherapy but almost always fatally recur. Using RNAseq data from 107 pairs pre- post-standard treatment locally recurrent IDHwt GBM tumours, we identified two responder subtypes based on therapy-driven changes in gene expression. In thirds patients a specific subset genes is up-regulated primary to recurrence (Up responders) one third same...
Abstract AIMS The rapid recurrence of therapy-resistant glioblastoma leaves patients with a dismal 2-year survival rate just 16%, highlighting the need to develop treatments that combat or prevent recurrence. Recently, have been stratified by their gene expression response therapy. Specifically, genes JARID2 binding sites in promoter (JBS-genes) either become up- down-regulated on progression from primary recurrent tumour. Importantly, these two responses appear employ different mechanisms...
Abstract AIMS Treating glioblastoma (GBM) patients remains challenging as the current regimens result in recurrence of a treatment-resistant and fatal tumour. We aimed to identify candidate pathways that, when mutated, confer treatment resistance. Targeting these may improve GBM effcacy. METHOD performed WGS WES on 46 matched primary recurrent GBMs (the Discovery cohort) used data from additional 188 samples Glioma Longitudinal AnalySiS consortium (GLASS: Validation cohort). First, we...
ABSTRACT Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors represent clinically relevant avatars. We created a large collection PDOXs from primary recurrent gliomas with without mutations in IDH1 , which retained histopathological, genetic, epigenetic transcriptomic features no mouse-specific clonal evolution....
Abstract AIMS Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Despite aggressive treatment, a resistant recurs practically all patients. We therefore aimed to better understand mechanisms driving this treatment resistance through investigating changes gene expression across pairs of and recurrent GBM tumours. METHOD generated or acquired bulk RNA sequencing data for first tumours from 107 patients who received standard treatment. Differential analysis between...