Cancer related research in NDM
Cancer is studied from several angles at NDM, from its epidemiology and potential causes, to its effect on patient lives and outcomes, as well as the basic science underpinning the unregulated cell growth that is the hallmark of the disease.
Interview with Professor Xin Lu
Professor Xin Lu is Director of the Ludwig Institute for Cancer Research, Oxford Branch. She has long standing research interests in tumour suppression and was one of the first researchers to show that the tumour suppressor p53 responds to both oncogene activation and DNA damaging signals. Her group was one of the first to demonstrate how to selectively activate p53 to kill cancer cells, through identification and characterization of the evolutionarily conserved ASPP family of proteins.
Q: How do cells change their characteristics and fate in response to external signals?
Xin Lu: The ability of cells to change their characteristics and fate in response to external signals is called cellular plasticity. This plasticity underlies cancer initiation, metastasis and resistance to therapy. Read more
Interview with Professor Simon Leedham
Professor Simon Leedham is a Cancer Research UK Clinician Scientist and an Honorary Consultant Gastroenterologist. His current research focuses on the cell-signaling pathways that control intestinal stem cells and the dysregulation of these pathways in cancer.
Q: What are intestinal stem cells and why are they susceptible to cancer?
Simon Leedham: Our intestines are organized into millions and millions of tiny flask like structures called crypts and each crypt contains a family of cells. The stem cells reside at the very bottom of these crypts and are like the head of the family. The stem cells divide and give rise to daughter cells, which move up the sides of the crypts. Read more
| Principal Investigator | Group name | Summary |
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Human Cancer Genetics | The long-term goals of my laboratory are to study the commonly inherited genetic variants, their influence on the origins, progression and treatment of human cancer, and their abilities to serve as easily accessible and measurable biomarkers in the clinic: identifying those at increased risk of developing cancer and worsened prognosis. |
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Medicinal Chemistry | Research in the Brennan group is focused on discovery of chemical probes for three classes of epigenetic enzymes, lysine demethylases (KDM), plant-homeodomains (PHD) and bromodomains (BRD). One of the KDMs, KDM4B is potentially import in breast cancer and the chemical probe my research group is developing will provide a chemical starting point for drug discovery if it proves the link between KDM4B and breast cancer. |
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Chromatin and Genome Integrity | Using transgenic mouse models and a combination of cell biology, biochemical, genomic and proteomic approaches, they are investigating the alterations that occur within DSB-associated chromatin as a result of the activities of these core proteins and other newly identified components of the DNA damage response. Moreover, we hope to elucidate how such changes determine DSB repair fate, to better understand why a breakdown in these processes can result in disease and cancer predisposition in humans. |
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ER-associated degradation | The lab’s principal focus is on ER-associated degradation (ERAD), a multifaceted process responsible for clearing non-functional and orphan translation products from the early secretory pathway. Ensuring the highest level of fidelity for the transiting protein load is essential, as unabated accumulation or exposure to the extracellular environment of misfolded proteins can negatively impact cellular homeostasis and viability |
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Cancer genomics and immunology | We are interested in the interaction between tumours and the host immune system, with a particular focus on those with a very high mutational load as a result of polymerase proofreading domain mutations. We have recently shown that ultramutated POLE-mutant colorectal and endometrial cancers have an excellent prognosis, plausibly because they elicit a strong anti-tumour T cell response against the many neoantigens they generate. Further study of these and other highly mutated cancers may provide novel insights into mutation as a cancer biomarker and therapeutic target. |
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Regulation of vascular growth | The goal of our research programme is to understand the transcriptional networks governing vascular growth during development and tumourigenesis. The highly organised processes of vascular development require the correct spatial and temporal expression of a large number of genes, and it is our aim to understand the transcriptional cascades that contribute to this control. Rapid proliferation of new blood vessels is a necessary step in the development and spread of solid tumours, and the disorganised and aberrant structure of these vessels presents a barrier to effective therapy. |
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Anti-viral T cell | The main objective of my group’s research is to focus on the functional aspects of the antigen specific T cells and studying the factors affecting T cells in controlling virus infection by utilizing well established in-vitro experiment models as well as well defined, large clinical cohorts with my collaborators in China and Vietnam. |
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Professor Panagis Filippakopoulos
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Epigenetic Signalling | The Filippakopoulos group together with others have demonstrated that it is possible to inhibit the function of BET family members by targeting their mechanism of action resulting in dramatic effects in disease, leading to potential therapies. This novel targeting mechanism based on the inhibition of protein interactions initiated by reader domains of chromatin modifications needs to be further explored in order to understand and explain transcription initiation. |
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Cell signalling, adhesion and pore formation in human disease | Our work is focused on molecular mechanisms underlying pathology in humans, specifically cancer and membrane pore formation and cell adhesion. We are studying mechanisms of 3' uridylation of RNAs with clear effects in tumourigenesis and are engaged in related translational research in collaboration with the Target Discovery Institute and Cancer Research Technology. |
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Melanoma | Our laboratory is interested in determining how a precise programme of transcription regulation is achieved, particularly in the transition between normal and cancer stem cells and their proliferating progeny, and the parallels with normal stem cell populations. |
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Chromosome Dynamics | The Green group study the processes that occur at replications forks and in replication factories in mammalian cells. These are likely to be physical cellular locations where the genome instability arises that can lead to cancer and other disorders. |
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Inflammation and innate immunity | We study molecular mechanisms governing pro-inflammatory signalling during innate immune responses. A central focus of the lab is to elucidate the role and regulation of non-degradative ubiquitin modifications in these processes. Ultimately, we aim to identify ubiquitin-handling factors that can be targeted to modulate inflammation and antagonize cancer. |
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Molecular mechanisms of colorectal cancer | I am interested in investigating how the metastatic niche influences secondary tumor outgrowth by inducing cancer-promoting functions, such as proliferation, ECM remodeling, migration, invasion and angiogenesis. |
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Cancer Research UK Receptor Structure Research Group | The group's research addresses fundamental questions about cell-cell signalling systems of importance to human health. How are signalling assemblies arranged? Which features are necessary for normal signal transduction into the cell? What mechanisms trigger dysfunctional signalling? The work ties into an extensive network of interdisciplinary local and international collaborations with the ultimate aim of learning how to manipulate these signalling systems for the design of new clinical therapies. |
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TDI mass spectrometry group | The Kessler group are analyzing a particular subset of the deubiquitylating enzyme family, containing an ovarian tumor domain (OTU). This conserved motif encodes for a potential cysteine protease, and is conserved throughout evolution. However, the function of this class of proteins is largely unknown. Their studies indicate a central role for OTUs, in particular OTUB1, in regulating cell invasion and morphology by modulating the stability of small GTPases. The impact of these molecular interactions are studied within the context of host-pathogen interactions and tumourigenesis. |
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Professor Stefan Knapp (Visiting professor)
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Phosphorylation Dependent Signalling Biology group | The Knapp group have generated a comprehensive set of high resolution crystal structures that cover most members of the protein family of interest. They are particularly interested in protein interactions module of the bromodomain family that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks as well as in protein kinases, a highly dynamic family of key signalling molecules. This effort generated several highly selective chemical probes in the kinase and bromodomain area as well as publications that describe structural properties of human protein families and structural mechanisms of their regulation. |
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Professor Skirmantas Kriaucionis
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Epigenetic Mechanisms | Our research program aims to elucidate the molecular function of DNA modifications in normal cells and cancer. We employ biochemistry and in vivo approaches to investigate roles of DNA modifications in transcription, heritability, mutability and nuclear organisation. Together with advancing knowledge of the basic biology of DNA, we delineate defects in cancer and aim to target them for the therapy. |
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Gastrointestinal Stem Cell Biology | Adult gastrointestinal stem cells are the targets of carcinogenic gene mutations and are believed to be the cells of origin of luminal gastrointestinal cancers. Our current research focuses on the homeostatic cell-signaling pathways that control intestinal stem cells and the dysregulation of these pathways in carcinogenesis. |
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Tumour Supression | The main goal of our research is to identify molecular mechanisms that control cellular plasticity and suppress tumour growth. Cells are able to change their characteristics and cell fate in response to external signals. This ability to change – cellular plasticity – underlies cancer initiation, metastasis and resistance to therapy. We are particularly interested in ‘guardians’ of plasticity in epithelial cells, from which over 80% of human tumours originate. We have a long-standing interest in the tumour suppressor p53 and the ASPP family of proteins (Apoptosis-Stimulating Protein of p53; Ankyrin repeats, SH3 domain and Prolin rich sequence containing proteins), which have several roles including regulation of p53. |
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Oxygen Sensing Group | Current lines of investigation include the general importance of prolyl hydroxylation as a signalling mechanism, the structural analysis of oxygen sensitive prolyl hydroxylases, the role of the HIF system in development, ischaemia/hypoxic disease, and tumour biology, and the interaction between oxygen and iron signalling |
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Functional Genomics | Our group develops new approaches to study signaling networks in cancer cells and to uncover specific weaknesses, particularly in breast and lung cancer, that can be used for developing more effective targeted drugs and for guiding treatment decisions. We use high-throughput chemical and genetic screening approaches and haploid genetics to engineer isogenic human cancer cells and tease out chemical and genetic interactions that could be therapeutically exploited. These interactions are then studied in more detail using cell culture, mouse models, and patient samples. |
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Gatrointestinal Genomics | The group analyse genome wide SNP tagging arrays, targeted amplicon resequencing and whole genome sequencing data with the aim of discovering genetic variants that affect susceptibility to colorectal cancer and Barrett’s oesophagus or which could be used to predict adverse drug responses to standard chemotherapeutics |
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The Nephrology Oxygen Sensing Group | The group has demonstrated that this involves a novel method of protein recognition in which oxygen sensitive prolyl hydroxylation of HIF regulates ineraction with the von Hippel-Lindau tumour suppressor E3 ubiquitin ligase. Current lines of investigation include investigating the effects of mutations in components of this pathway both in vitro and in vivo, using molecular probes to examine the role of the HIF system in development, ischaemia/hypoxic disease, and tumour biology and investigating how this pleiotropic system can be manipulated for benefit in a variety of disease states. |
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Professor Sir Peter J Ratcliffe FRS
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Hypoxia Biology Group | The laboratory works on understanding the mechanisms by which cells sense and signal hypoxia (low oxygen levels). Oxygen is of fundamental importance for most living organisms, and the maintenance of oxygen homeostasis is a central physiological challenge for all large animals. Hypoxia is an important component of many human diseases including cancer, heart disease, stroke, vascular disease, and anaemia. |
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Quantitative Biological Imaging | The aim of the research is to enhance our understanding of complex biological processes through the analysis of image data that has been acquired at the microscopic scale. Jens Rittscher develops algorithms and methods that enable the quantification of a broad range of phenotypical alterations, the precise localisation of signalling events, and the ability to correlate such events in the context of the biological specimen. |
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Computational Genomics | Research shows us that different patients with the same type of cancer are very different at the genomic level. It is crucial to understand which mutations are driving the cancer, which specific mutations are important for the progression of the disease. In order to identify these driver mutations we need to have an overall likelihood for mutations in the genome on average. It is hoped that these discoveries will in the future contribute to personalised medicine. |
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Chemical Epigenetics | The goal of our research is to develop and apply novel tools to probe epigenetic modifications, thereby understanding their functions in human health and disease. To do so, we combine various chemical biology, biophysics and genomic approaches to analyze the epigenome. We also utilize the epigenetic information in body fluids for non-invasive for disease diagnostics, including early detection of cancer. In addition, we are investigating the epigenetic heterogeneity of tumors to understand the contribution of epigenetics to cancer. |
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Molecular and Population Genetics | The group works on the identification of genes that predispose to colorectal and other cancers. His research focuses on the relative importance of selection and genomic instability. Identifying genes that increase the risk of bowel or other cancers allows us to offer preventative measures, such as removing tumours at an early stage. A better understanding of how and why cancers grow also helps develop improved treatments. |
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Professor Benoit Van Den Eynde
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Immune responses to cancer | The Van Den Eynde group studies immune responses to cancer, with the long-term goal of harnessing the immune system to fight cancer. |
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Protein Crystallography | The overall aim of Dr von Delft's research is to establish methods to ensure that X-ray structures can serve as a routine and predictive tool for generating novel chemistry for targeting proteins - as opposed to them being only occasionally and retrospectively useful descriptively, as is currently generally the case. It is hoped that this technology can be used in the discovery of new drugs. |
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Translational Computational Oncogenomics | The focus of my group is the development of computational methods for understanding data coming out of modern studies in genetics using next generation sequencing technologies. |
