A5026287626- Cancer Cells and Metastasis
- Amyotrophic Lateral Sclerosis Research
- Cancer, Hypoxia, and Metabolism
- Neurogenetic and Muscular Disorders Research
- Cancer Genomics and Diagnostics
- Complement system in diseases
- MicroRNA in disease regulation
- Endoplasmic Reticulum Stress and Disease
- Pancreatic and Hepatic Oncology Research
- Immunotherapy and Immune Responses
- Hippo pathway signaling and YAP/TAZ
- Nanoparticle-Based Drug Delivery
- Ubiquitin and proteasome pathways
- Autophagy in Disease and Therapy
- Neuroblastoma Research and Treatments
- Immune Cell Function and Interaction
- Protein Degradation and Inhibitors
- biodegradable polymer synthesis and properties
- Cancer Research and Treatments
- Cancer-related molecular mechanisms research
- Metabolism, Diabetes, and Cancer
- Adipose Tissue and Metabolism
- Nanoplatforms for cancer theranostics
- Circular RNAs in diseases
- Drug-Induced Hepatotoxicity and Protection
Centre for Human Genetics
2021-2023
University of Oxford
2021-2023
Imperial College London
2015-2022
Hammersmith Hospital
2015-2020
Imperial Valley College
2012
Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5−ve regenerative cell populations (RSCs), characterized fetal transcriptional profiles. Neoplasia hijacks signaling, so we assessed distribution CBCs and RSCs mouse human intestinal tumors. Using combined molecular-morphological analysis, demonstrate variable expression markers across a range lesions. The degree CBC-RSC admixture was...
Abstract Neuroblastoma is the most common paediatric solid tumour and prognosis remains poor for high-risk cases despite use of multimodal treatment. Analysis public drug sensitivity data showed neuroblastoma lines to be sensitive indisulam, a molecular glue that selectively targets RNA splicing factor RBM39 proteosomal degradation via DCAF15-E3-ubiquitin ligase. In models, indisulam induces rapid loss RBM39, accumulation errors growth inhibition in DCAF15-dependent manner. Integrative...
Defects in energy metabolism are potential pathogenic mechanisms amyotrophic lateral sclerosis (ALS), a rapidly fatal disease with no cure. The through which this occurs remain elusive and their understanding may prove therapeutically useful. We used metabolomics stable isotope tracers to examine metabolic changes well-characterized cell model of familial ALS, the motor neuronal NSC-34 line stably expressing human wild-type Cu/Zn superoxide dismutase (wtSOD1) or mutant G93A (G93ASOD1). Our...
Methylenetetrahydrofolate dehydrogenase (NAD(P)+ dependent) 2, methenyltetrahydrofolate cyclohydrolase (MTHFD2) is a mitochondrial enzyme involved in folate metabolism. A number of recent studies have highlighted this as being highly expressed many solid tumors, including breast cancer, and to be correlated with poor survival. However, the metabolic functions MTHFD2 cancer cells not been well-defined. To investigate function cells, we generated characterized MCF-7 stable suppression...
VCP/p97 regulates numerous cellular functions by mediating protein degradation through its segregase activity. Its key role in governing homoeostasis has made an appealing anticancer drug target. Here, we provide evidence that acts as a regulator of metabolism. We found was tied to multiple metabolic processes on the gene expression level diverse range cancer cell lines and patient-derived myeloma cells. Cellular dependency maintain proteostasis increased under conditions glucose glutamine...
An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses these tumors still a challenge. Using an integrated screening approach identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as druggable target, which when inhibited improved radiotherapy, even displaying features CD8+ infiltration. While well-known for its role the immune...
Abstract The cellular mechanisms that control protein degradation may constitute a non-oncogenic cancer cell vulnerability and, therefore, therapeutic target. Although this proposition is supported by the clinical success of proteasome inhibitors in some malignancies, most cancers are resistant to inhibition. ATPase valosin-containing (VCP; p97) an essential regulator multiple pathways and has emerged as target for therapy. We found pharmacological depletion VCP enzymatic activity with...
Abstract Exposure to aristolochic acid (AA) is associated with human nephropathy and urothelial cancer. The tumour suppressor TP53 a critical gene in carcinogenesis frequently mutated AA-induced tumours. We investigated the impact of p53 on AAI-induced nephrotoxicity DNA damage vivo by treating Trp53 (+ / +), −) (− mice 3.5 mg/kg body weight (bw) AAI daily for 2 or 6 days. Renal histopathology showed gradient intensity proximal tubular injury from +) mice, especially after observed renal was...
The rate of disease progression in amyotrophic lateral sclerosis (ALS) is highly variable, even between patients with the same genetic mutations. Metabolic alterations may affect course variability ALS patients, but challenges identifying preclinical and early phases limit our understanding molecular mechanisms underlying differences progression. We examined effects SOD1G93A on thoracic lumbar spinal cord metabolites two mouse models different rates progression: transgenic...
The monocarboxylate transporter 1 (MCT1) is a key element in tumor cell metabolism and inhibition of MCT1 with AZD3965 undergoing clinical trials. We aimed to investigate nutrient fluxes associated by identify possible biomarkers drug action. synthesized an 18F-labeled lactate analogue, [18F]-S-fluorolactate ([18F]-S-FL), that was used alongside [18F]fluorodeoxyglucose ([18F]FDG), 13C-labeled glucose lactate, the modulation diffuse large B-cell lymphoma models NOD/SCID mice. Comparative...
Non-cell autonomous processes involving astrocytes have been shown to contribute motor neuron degeneration in amyotrophic lateral sclerosis. Mutant superoxide dismutase 1 (SOD1G93A) expression is selectively toxic neurons co-culture, even when mutant protein expressed only and not neurons. To examine metabolic changes astrocyte-spinal co-cultures, we carried out metabolomic analysis by 1H NMR spectroscopy of media from co-cultures astrocyte-only cultures. We observed increased glucose uptake...
Abstract Understanding the normal temporal variation of serum molecules is a critical factor for identifying useful candidate biomarkers diagnosis and prognosis chronic disease. Using small RNA sequencing in longitudinal study 66 women with no history cancer, we determined distribution dynamics (via intraclass correlation coefficients, ICCs) miRNA profile over 3 time points sampled across 2–5 years course screening trial, UKCTOCS. We were able to define subset longitudinally stable miRNAs...
Abstract In homeostasis, counterbalanced morphogen signalling gradients along the vertical axis of intestinal mucosa regulate fate and function epithelial stromal cell compartments. Here, we used a disease-positioned mouse, human tissue, to explore consequences pathological Bone Morphogenetic Protein (BMP) dysregulation on epithelial- mesenchymal interaction. Aberrant pan-epithelial expression secreted BMP antagonist GREM1, resulted in ectopic crypt formation with lineage tracing...
Neuroblastoma is the most common solid tumour in childhood and prognosis remains poor for high-risk cases despite use of multimodal treatment. Analysis public drug sensitivity data showed neuroblastoma lines to be particularly sensitive indisulam, a molecular glue that selectively targets RNA splicing factor RBM39 proteosomal degradation via DCAF15-E3-ubiquitin ligase. In models, indisulam induced rapid loss RBM39, accumulation errors growth inhibition DCAF15- dependent manner. Integrative...
Abstract An immunosuppressive microenvironment causes poor tumour T-cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses these tumours still a challenge. Using an integrated screening approach identify cancer-specific vulnerabilities, we complement receptor C5aR1 as druggable target which when inhibited improves radiotherapy even displaying features CD8+ infiltration. While well-known for its role the immune...
Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5-ve regenerative cell populations (RSCs), characterised fetal transcriptional profiles. Neoplasia hijacks signalling, so we assessed distribution CBCs and RSCs mouse human intestinal tumors. Using combined molecular-morphological analysis demonstrate variable expression markers across a range lesions. The degree CBC-RSC admixture was...
<h3>Introduction</h3> Current management of rectal cancers (RC) includes radiotherapy as these low tumours have a fixed position within the pelvis. Response to can be highly variable, with data from S:CORT consortium showing negative association between tumour response radiation and TGFβ activation status. The pleiotrophic morphogen TGF is implicated in fibroblast immune cell evasion, inhibition enhancing radiosensitivity mouse lung cancer model (Lan et al., 2021). Here we established...