A5012575170- RNA modifications and cancer
- Cancer-related gene regulation
- RNA Research and Splicing
- Lung Cancer Treatments and Mutations
- Pancreatic and Hepatic Oncology Research
- Cancer-related molecular mechanisms research
- Cancer Research and Treatments
- Cell Image Analysis Techniques
- Cancer, Hypoxia, and Metabolism
- Hormonal Regulation and Hypertension
- Phagocytosis and Immune Regulation
- Protein Kinase Regulation and GTPase Signaling
- Cancer Genomics and Diagnostics
- Cancer-related Molecular Pathways
- Single-cell and spatial transcriptomics
- Ubiquitin and proteasome pathways
- Genomics and Chromatin Dynamics
- PI3K/AKT/mTOR signaling in cancer
- Metabolism, Diabetes, and Cancer
- Pleural and Pulmonary Diseases
- Eicosanoids and Hypertension Pharmacology
- Microtubule and mitosis dynamics
- Occupational and environmental lung diseases
- Glutathione Transferases and Polymorphisms
- Caveolin-1 and cellular processes
AstraZeneca (United Kingdom)
2022-2024
University of Glasgow
2015-2023
CRUK Lung Cancer Centre of Excellence
2021-2023
University College London
2021-2023
Cancer Research UK Manchester Institute
2018-2023
University of Manchester
2018-2023
Cancer Research UK
2021-2023
Abstract MYC is implicated in the development and progression of pancreatic cancer, yet precise level deregulation required to contribute tumor has been difficult define. We used modestly elevated expression human MYC, driven from Rosa26 locus, investigate phenotypes arising mice an approximation trisomy. show that this alone suffices drive neuroendocrine tumors, accelerate KRAS-initiated precursor lesions metastatic ductal adenocarcinoma (PDAC). Our phenotype exposed suppression type I...
Abstract Image-based profiling has emerged as a powerful technology for various steps in basic biological and pharmaceutical discovery, but the community lacked large, public reference set of data from chemical genetic perturbations. Here we present generated by Joint Undertaking Morphological Profiling (JUMP)-Cell Painting Consortium, collaboration between 10 companies, six supporting two non-profit partners. When completed, dataset will contain images profiles Cell assay over 116,750...
KRAS is the most frequently mutated driver oncogene in human adenocarcinoma of lung. There are presently no clinically proven strategies for treatment KRAS-driven lung cancer. Activating mutations thought to confer independence from upstream signaling; however, recent data suggest that this may not be absolute. We show initiation and progression tumors require input ERBB family receptor tyrosine kinases (RTKs): Multiple RTKs expressed active earliest stages tumor development, with a...
Abstract Exploiting oxidative stress has recently emerged as a plausible strategy for treatment of human cancer, and antioxidant defenses are implicated in resistance to chemotherapy radiotherapy. Targeted suppression could thus broadly improve therapeutic outcomes. Here, we identify the AMPK-related kinase NUAK1 key component response pathway reveal specific requirement this role colorectal cancer. We show that is activated by activation required facilitate nuclear import master regulator...
PROteolysis TArgeting Chimeras (PROTACs) use the ubiquitin–proteasome system to degrade a protein of interest for therapeutic benefit. Advances made in targeted degradation technology have been remarkable, with several molecules having moved into clinical studies. However, robust routes assess and better understand safety risks PROTACs need be identified, which is an essential step toward delivering efficacious safe compounds patients. In this work, we used Cell Painting, unbiased...
Abstract Wild-type KRAS ( WT ) amplification has been shown to be a secondary means of activation in cancer and associated with poor survival. Nevertheless, the precise role overexpression lung progression is largely unexplored. Here, we identify characterize KRAS-responsive lncRNA, KIMAT1 (ENSG00000228709) show that it correlates levels both cell lines specimens. Mechanistically, MYC target drives tumorigenesis by promoting processing oncogenic microRNAs (miRNAs) through DHX9 NPM1...
Abstract In image-based profiling, software extracts thousands of morphological features cells from multi-channel fluorescence microscopy images, yielding single-cell profiles that can be used for basic research and drug discovery. Powerful applications have been proven, including clustering chemical genetic perturbations based on their similar impact, identifying disease phenotypes by observing differences in between healthy diseased cells, predicting assay outcomes using machine learning,...
NUAK1 is a member of the AMPK-related family kinases. Recent evidence suggests that an important regulator cell adhesion and migration, cellular organismal metabolism, regulation TAU stability. As such, may play key roles in multiple diseases ranging from neurodegeneration to diabetes metastatic cancer. Previous work revealed crucial role for supporting viability tumour cells specifically when MYC overexpressed. This surprising, given activated by suppressor LKB1. Here we show that, lacking...
Abstract Chromosomal instability (CIN) is a driver of clonal diversification and intratumor heterogeneity, providing genetic diversity that contributes to tumor progression. It estimated approximately 80% solid cancers, including non–small cell lung cancer (NSCLC), exhibit features CIN, which affects growth response therapy. However, the molecular mechanisms connecting CIN progression are still poorly understood. Through an RNAi screen performed on genes involved in overexpressed human...
While the use of bioluminescent proteins for molecular imaging is a powerful technology to further our understanding complex processes, fluorescent labeling with visible light such as GFP and RFP suffers from poor tissue penetration high background autofluorescence. To overcome these limitations, we generated an inducible knock-in mouse model iRFP713. This was used assess Cre activity in Rosa Cre-ER quantify upon different tamoxifen treatments several organs. We also show that iRFP can be...
Asbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations.
Inducible genetically defined mouse models of cancer uniquely facilitate the investigation early events in progression, however, there are valid concerns about ability such to faithfully recapitulate human disease. We developed an inducible model progressive lung adenocarcinoma (LuAd) that combines sporadic activation oncogenic KRasG12D with modest overexpression c-MYC (KM model). Histological examination revealed a highly reproducible spontaneous transition from low-grade locally invasive...
Abstract KRAS is the most frequently mutated driver oncogene in human adenocarcinoma of lung. There are presently no clinically proven strategies for treatment KRAS-driven lung cancer. Activating mutations thought to confer independence from upstream signaling, however recent data suggest that this may not be absolute. Here we show initiation and progression tumors requires input ERBB family RTKs: Multiple RTKs expressed active earliest stages driven tumor development, with a multi-ERBB...
The NanoBiT Biochemical Assay (NBBA) was designed as a biochemical format of the cellular assay, aiming to screen weak protein-protein interactions (PPIs) in mammalian cell lysates. Here we present High Throughput Screening (HTS) application NBBA small molecule and fragment libraries identify compounds that block interaction KRAS-G12D with phosphatidylinositol 3-kinase (PI3K) p110α. This promotes PI3K activity, resulting promotion growth, proliferation survival, is required for tumour...
Inducible genetically defined mouse models of cancer uniquely facilitate the investigation early events in progression, however there are valid concerns about ability such to faithfully recapitulate human disease.  We developed an inducible model progressive lung adenocarcinoma (LuAd) that combines sporadic activation oncogenic KRasG12D with modest overexpression c-MYC (KM model). Histological examination revealed a highly reproducible transition from adenoma locally invasive within...
ABSTRACT Hypothesis Asbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations. Methods Genetically modified conditional allelic mice that were previously shown develop in absence exposure asbestos induced with lentiviral vector expressing Cre recombinase and without intrapleural injection amosite monitored until symptoms required euthanasia. Resulting tumours examined histologically by immunohistochemistry for expression...
Summary PROTACs (PROteolysis TArgeting Chimeras) use the ubiquitin-proteasome system to degrade a protein of interest for therapeutic benefit. Advances in targeted degradation technology have been remarkable with several molecules moving into clinical studies. However, robust routes assess and better understand safety risks need be identified, which is an essential step towards delivering efficacious safe compounds patients. In this work, we used Cell Painting, unbiased high content imaging...
<p>Downregulation of MYC and KRAS signalling</p>