NIHRDataInsights/HRCSData huggingface dataset:
Title: Exploring the active chromatin landscape in oesophageal adenocarcinoma
Funder: Wellcome Trust

Abstract: Oesophageal adenocarcinoma (OAC) is a cancer with poor prognosis and increasing incidence. Little is known about the molecular regulation underlying the onset of OAC from its precursor states. Improving our understanding here may lead to the development of novel clinical options, improving patient outcomes. Change in the cell states of OAC precursors may be established through signalling-mediated changes to the chromatin landscape. These changes can modify cellular phenotype in terms of signalling and survival, leading to cancer. In this project, we aim to characterise the regions of chromatin that become accessible, or open, in the context of OAC and whether the regions that change possess function as enhancers. This is important as these enhancers may be drive the transition to OAC. To do this, a range of 'omics technologies will be used to characterise the open OAC transcriptome, and identify regions with enhancer function. Bioinformatics-based approaches will be used to validate the identified enhancers. Enhancer functionality will be explored by manipulation in OAC cell lines, using siRNA and CRISPR-based approaches. This work will potentially identify novel therapeutic targets and biomarkers for OAC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Understanding the mechanistic basis of PARG inhibitor sensitivity in the context of high-grade serous ovarian cancer.
Funder: Wellcome Trust

Abstract: DNA damage repair (DDR) is frequently activated during normal cellular contexts and is thus instrumental during tumourigenesis when functioning aberrantly. For example, DDR defects are widespread amongst ovarian cancers (1) and thus genomic instability is a defining characteristic of this cancer type (2). Hence, DDR research is extensive, providing insights into mechanisms, therapies and biomarkers. One such research avenue involves the DNA repair enzyme PARG (3), whose inhibitor (PARGi) has shown potential therapeutic usages (4). To widen the opportunities of PARGi as a therapeutic agent, one must first dissect the mechanism of differing PARGi sensitivity. Therefore, a screen identifying genes which, when defective, sensitise cells to PARGi was performed (4), and identified TIMELESS. We aim to decipher the functions of TIMELESS in DDR and PARG dynamics with a focus on TIMELESS’s structure-function relationship. The approach is three-fold: firstly, generation of a series of TIMELESS mutants, with targeted residues spanning the entire gene sequence, followed by characterising the mutants using proliferation and &gamma;H2AX-production as quantitative outputs. Secondly, hypothesis-driven cell biology-based experiments to focus on the DDR roles of TIMELESS. Finally, an unbiased approach employing mass spectrometry will characterise replication fork modifications upon TIMELESS mutations.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Investigating how winners alter losers in Minute cell competition
Funder: Wellcome Trust

Abstract: I work on cell competition, a process where relatively less fit cells (losers) are eliminated by relatively fitter neighbouring cells (winners). There are many types of cell competition and in my PhD I will focus on Minute cell competition. In Minute cell competition cells that have lost one copy of a ribosome gene (called Minute) are induced to die by wild-type cells. Minute cell competition acts as a quality control to maintain tissues healthy and is likely to contribute to the elimination of cells with tumorigenic potential. We are interested in understanding how proximity with winner cells modifies the cellular state of Minute cells so that they behave as losers and die. Our approach involves introducing groups of wild-type-cells in a Minute background in developing fly epithelia. In my work I will characterise how cell competition changes specific cellular processes such as translation, autophagy and oxidative stress. I will also look at gene expression changes induced during cell competition in loser Minute cells, to identify novel additional factors affected by winners and involved in cell competition. This work is likely to identify new components that, by modulating cell competition, could be important in maintaining tissue health and in cancer prevention.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: What influences cancer services uptake in Ghana and how can this information support policy-making?
Funder: Wellcome Trust

Abstract: My research is about what influences people in Ghana to use cancer services. Cancer is an increasing problem in Ghana due to changes to lifestyle and population age. Many things influence cancer services use including, disease beliefs, stigma, healthcare trust, and costs. The Ghanaian health system seeks to expand cancer services in a way that benefits as many as possible, but challenges remain in understanding why some patients do not attend. I plan to use mixed methods to explore what influences cancer service use and how this information can be useful for Ghanaian policymakers. A key stage will involve surveying public members’ beliefs and behaviours. I will analyse data collected to see how information about age, gender and job relate to peoples’ views and might influence whether they would use cancer services; I also hope to build profiles of types of people to help policymakers target help to those most in need. To further understand and check the analysis, I will use narrative interviews with a range of the public to listen to what they think and why they act as they do. I will bring together the findings and discuss with policymakers how this could help inform their decision-making.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Defining the structural mechanism of the cellular response to DNA inter-strand crosslinks: structural characterization and inhibition of SLF1-SLF2 with its interacting partners.
Funder: Wellcome Trust

Abstract: Interstrand crosslinks (ICLs) are the most toxic form of DNA damage, forming a blockage to essential cellular processes by preventing separation of the two strands of our DNA. DNA crosslinking agents that induce this form of damage have been at the frontline of chemotherapy for over 50 years. However, to protect our genomes from their constant exposure to DNA damage sources, our cells have specialised repair pathways to detect and remove ICLs. Understanding the molecular details of DNA damage repair pathways is therefore essential for advancing cancer research. Using a range of structural techniques and functional assays, including X-Ray crystallography and Cryo-EM, I will focus on a structurally uncharacterised complex involved in recruiting SMC (structural maintenance of chromosome) 5/6 to sites of double strand breaks (DSBs) introduced during the Fanconi Anaemia pathway, a major ICL repair pathway in proliferating cells. This complex, SLF1-SLF2, directly interacts with the E3 ubiquitin ligase, Rad18, which binds sites of DSBs marked by post-translational modifications, appearing to define a linear recruitment pathway for SMC5/6. This study will provide further insight into how toxic ICLs are resolved and could identify novel interactions that can be specifically inhibited for development of new cancer treatments to enhance chemotherapy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Mechanisms of NK cell activating receptor signalling at immune-tumour synapse and how it synergises with integrin signalling
Funder: Wellcome Trust

Abstract: Natural killer (NK) cells play a key role in our first line of defence against cancer and infectious diseases. NK cells achieve this through activating and inhibitory receptors that survey proteins on nearby cells through the formation of an immune synapse. Healthy cells express surface proteins that bind to inhibitory receptors and dampen the activating signals, whereas abnormal cells have either too many activating signals or too few inhibitory signals, which results in their killing by NK cells. Adhesion receptors, known as integrins, harmonise with NK cell receptors and cytoskeletal proteins to form the immune synapse and subsequent NK cell killing. I aim to gain a greater insight into the activating receptor, NKG2D. I will do this using an approach known as proximity labelling (PL). I will add labels onto proteins of interest (baits) and in specific conditions, these baits will label nearby proteins (prey). Using mass spectrometry, the prey will then be identified and validated for function. The application of PL on NKG2D can help uncover new protein associations (both signalling proteins and receptors) and provide insight into its link with adhesion signalling. This can inform future therapeutic targeting strategies or even discover novel targets for future cancer treatments.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Characterising the Novel Role of Inositol-5 Phosphatase B in B Cell Receptor Activation, Endocytosis and Signalling
Funder: Wellcome Trust

Abstract: White blood cells (WBCs) play a fundamental role in coordinating our immune system in response to infection. WBCs known as B cells produce antibodies and contribute to lasting immunity upon re-exposure to the same infection. Unfortunately, B cells are also responsible for various immune disorders and lymphatic cancers. This makes understanding the mechanisms controlling B cell behaviour vital for treating these diseases. B cell physiology is heavily regulated by a cell surface receptor known as the B cell receptor (BCR). We have uncovered a novel mechanism by BCR function is mediated through a specific enzyme that targets fat-like molecules called lipids. I aim to understand this previously unappreciated mechanism of regulation using a multidisciplinary approach. I will use biochemical and mass spectrometric approaches to determine how these enzymes are recruited to BCRs. I will genetically engineer cell lines which lack these enzymes to explore the functional impacts of their absence on BCR activation and signalling, measuring changes using flow cytometry and cutting-edge live-cell microscopy. Validating these enzymes as critical for BCR function will not only enhance our overall understanding of this complex process but also reveal new targets for therapeutic intervention.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Role of mixed lineage leukaemia (MLL) proteins 1 and 2 during mesoderm differentiation
Funder: Wellcome Trust

Abstract: In the early mammalian embryo, there is a clump of identical “naïve pluripotent” cells. After implantation in the mother’s uterus, these cells diverge into a multitude of different cell types during a process called gastrulation. During this process, the three main lineages of the mammalian body, ectoderm, mesoderm and endoderm, are formed and shortly after, the basic body plan and body axes are established. Here, we focus on formation of mesoderm that gives rise to cell types such as blood cells.While every cell in our body is in principle equipped with an exact copy of the same genetic information, in the form of DNA wrapped around proteins called histones, it is poorly understood how protein complexes that modify these histones, such as the MLL/COMPASS complex, control the process of mesoderm differentiation.To address this, I will use advanced imaging techniques that can watch individual MLL/COMPASS or the DNA sites to which they bind. I will use embryonic stem cells that mimic in a dish the changes that occur as pluripotent cells differentiate towards mesoderm.We hope to understand the driving forces behind the transition from pluripotent cells towards mesoderm lineages, providing overarching mechanistic principles of lineage diversification.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Characterisation and modulation of CTLA-4 trafficking: Focus on reversible ubiquitylation
Funder: Wellcome Trust

Abstract: Cancer immunotherapy harnesses the potency of the immune system to reinvigorate anti-tumour effects. CTLA-4 is a protein that acts as a brake on the immune system; blocking CTLA-4 can disengage the brake on immune cells, thereby freeing our immune system to attack tumours. Although therapies entailing a CTLA-4 blockade has led to promising results, they have yet to achieve their full clinical potential. To improve CTLA-4-targeting treatment, a thorough understanding of CTLA-4 function at the cell biology level is essential. Modulating the number of CTLA-4 present on the surface of immune cells is an emerging therapeutic strategy in cancer immunotherapy. Generally, protein levels at the cell surface are controlled by two major events: protein internalisation and transport to the cell surface. Very often, internalised proteins that will be degraded by the cell’s “garbage disposal system” are temporarily tagged by ubiquitin, which will later be removed by an enzyme. Here, we aim to explore how CTLA-4 traffics in the immune cells by 1) identifying the key proteins that regulate CTLA-4 levels on the cell surface and 2) characterising the enzymes that control CTLA-4 degradation using state-of-the-art screening approaches.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Understanding adult human hematopoiesis in ageing and chemotherapy
Funder: Wellcome Trust

Abstract: The resilience of the human hematopoietic system declines with age as it becomes more susceptible to age-related disorders or malignancies, produces lower blood counts and is less capable of fighting off infections. When subjected to chemotherapy, it can be severely challenged, but cell counts will usually recover in 2 to 3 weeks. However, in older patients, the recovery can be slower, and individuals over the age of 75 are unable to tolerate more intense regimens. In my project, I will compare and contrast the clonal composition and functional characteristics of hematopoietic cells from patients before and after receiving chemotherapy. To achieve this, blood samples of consenting patients between the ages of 40 and 90 will be obtained before and after their treatment, and I will grow single-cell derived colonies and then profile their DNA and single-cell RNA. This will allow me to measure how perturbation of the systemic environment affects the clonal composition of blood, how the proliferative capacities of cells are affected and what functional changes occur in their transcriptomes. This study will help us understand to what extent the fitness of hematopoietic stem cells is environment-dependent and how ageing affects the recovery time after chemotherapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Structural and mechanistic investigations of the SWI/SNF chromatin remodeller
Funder: Wellcome Trust

Abstract: Packaging the two metres of chromosomal DNA found in every human cell is achieved by wrapping DNA around histone proteins in complexes called nucleosomes. Generally, DNA wrapped within nucleosomes is rendered inaccessible to enzymes and DNA-binding factors involved in normal DNA processes such as gene expression, DNA damage repair and chromosome replication. Chromatin remodellers are large molecular machines that disrupt the interaction between DNA and histones, exposing the DNA and therefore making it accessible for fundamental biological processes. I will be focussing on a particular chromatin remodeller called SWI/SNF that uses chemical energy to move, modify and eject nucleosomes. Around 20% of human tumours have been shown to have mutated SWI/SNF, highlighting the complex as one of the most commonly affected targets in cancer. The aim of my project is to use structural (cryo-EM) and single molecule (FRET) analysis to probe the molecular details of the interaction of SWI/SNF with the nucleosome. Moreover, we will visualise SWI/SNF in action, in an attempt to understand how the machine remodels nucleosomes and leading to further understanding of its role in cancer. Our results will provide a platform for the future development of drugs that specifically target mutated SWI/SNF complexes in numerous cancers.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Exploiting SUMOylation to target MYC-driven cancers
Funder: Wellcome Trust

Abstract: MYC is a protein which is known to contribute to the development of cancer. It is found in many different types of cancer cells at much higher levels than it would be in healthy cells. As a result, MYC has been identified as a protein that could be targeted to treat cancer patients. However, developing a drug that inhibits MYC directly has proved challenging. Therefore, scientists have instead focused on targeting MYC indirectly. For example, several genes have been identified that when inhibited, result in the death of only cells that have too much MYC, such as cancer cells. This means that healthy cells with normal levels of MYC will not be affected. An example of one such gene is SAE2. SAE2 is an enzyme which catalyses the first step in a series of reactions called the SUMOylation pathway. Although this is an encouraging observation, it remains unclear why inhibiting SAE2 kills cancer cells with too much MYC. Therefore, the aim of my project is to find out why and how SAE2 inhibitors kill these MYC-overexpressing cancer cells. This will help determine whether we can use SAE2 inhibitors to treat cancer patients whose tumours possess too much MYC.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Determining the roles of the Artemis nuclease in genome stability at the replication fork
Funder: Wellcome Trust

Abstract: Damage to DNA occurs constantly within our cells. If this damage is not repaired, it can lead to mutations in our genome when cells divide, which can cause cancer. So, to protect the integrity of our DNA, cells have evolved a variety of mechanisms to fix these lesions. One protein that plays a key role in these processes is Artemis, which acts in the repair of several different forms of damage by incising sections of damaged DNA. I will study this protein using a range of biochemical, genetic and cell biology techniques. These will characterise the reactions that Artemis catalyses at sites of DNA damage, whether it requires interacting partners or modifications to do so and will enhance our understanding of the functions of each of its domains. I will also be collaborating with chemists to develop inhibitors against Artemis. By better understanding the mechanisms that protect our DNA at the molecular level, we can improve cancer treatments. Chemotherapeutic drugs often kill tumour cells by damaging their DNA and cancers can evolve resistance to these treatments by increasing their capacity for repair. Inhibitors targeting Artemis could therefore be used to help overcome resistance to chemotherapeutic drugs and radiotherapy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Mechanisms of RUNX1 regulation in human developmental haematopoiesis and childhood leukaemia
Funder: Wellcome Trust

Abstract: All adult blood cells are derived from prenatal blood stem cells produced in the embryo, where the process is dependent on a gene named RUNX1. Blood cell formation and the development of various blood cancers (leukaemia) are sensitive to RUNX1 levels. In my DPhil, I will characterise the mechanisms regulating RUNX1 levels in normal and malignant human blood cell formation. I will use a “test tube” experimental approach to model human fetal blood cell formation, by differentiating stem cells into immature blood cells (progenitors). I will characterize the dynamic regulatory changes in the RUNX1 genomic region at distinct blood progenitor stages. These data will form the benchmark for the examination of RUNX1 regulation in primary human blood progenitor cells and childhood acute lymphoblastic leukaemia (ALL) samples. Lastly, RUNX1 regulation will be perturbed through genetic and epigenetic engineering, to identify the contribution of aberrant RUNX1 expression to the development of childhood leukaemia. This comparative approach will help us understand not only regulatory mechanisms of normal human blood cell formation, and how well this process can be modelled in a test tube, but also how altered regulation of RUNX1 affects leukaemia development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS
Title: Community effects in epithelial-mesenchymal transition
Funder: Wellcome Trust

Abstract: At different stages in life some cells acquire the ability to wander from one site to another through a process called epithelial-mesenchymal transition (EMT). This process is essential during development because it ensures that specialised cells form tissues in the right place at the right time. EMT remains important later in life, too, for mechanisms such as wound healing and tissue remodelling. However, EMT is also linked to pathologies including fibrosis and cancer metastasis. Here, we seek to distinguish epithelial cells from wandering mesenchymal cells and then investigate how the decision to undergo EMT is triggered. We hypothesise that EMT can be spread to the cell’s neighbourhood and that this spread depends on a critical starting number of EMT inducing cells, which helps maintain conformity in the community. Understanding how cells decide to migrate and how their neighbours respond to this change will give us an insight in normal developmental processes and has potential to reveal markers for metastatic cancer types and molecular targets to prevent metastasis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS