Can we use epigenetic profiles related to e-cigarette use to predict the potential harms and relative safety of e-cigarette use compared with smoking for cancer risk? 

Contact: Rebecca Richmond

Context: DNA methylation is a type of epigenetic modification which is strongly influenced by tobacco smoke and has been found to predict the development of cancer. We have recently established that the DNA methylation profile of e-cigarette use in non-smokers is distinct from that of smokers. The aim of this project is to investigate the extent to which this DNA methylation is predictive of cancer incidence and development, which might give insights into the relative safety of e-cigarette use.

How well can we predict cancer risk and incidence using estimates of stochastic epigenetic variation in peripheral tissues? 

Contact: Matthew Suderman

Context: Increases in stochastic variation in DNA methylation have been linked to biological aging and increased risk of cancer and even hypothesized to play a key role in evolution. A variety of approaches have been proposed for identifying this variation and its associations with phenotypes and exposures. The aim of this project is to systematically evaluate how well each approach applied to peripheral blood DNA methylation predicts cancer risk and/or incidence and to propose a new approach with improved performance.

Can we identify novel factors that causally affect circulating Prostate-specific antigen (PSA) levels?

Contact Richard Martin

Context: (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, intrinsic (e.g. BMI, inflammation & genetics) and extrinsic (e.g. cycling) can impact PSA, with implications for false negative and positive results. The aim here is to identify previously unknown factors 'omic and other metabolic factors that may impact on PSA-based detection & surveillance.

Are microbiome derived circulating metabolites causally associated with cancer risk or progression?

Contact: Kaitlin Wade

Context: The human gut microbiome has been linked to some cancers, especially those of the colon but studies have been small and prone to various biases. The aim of this project is to use naturally occurring variation in genes encoding microbiome derived circulating metabolites to be used as proxies for these targets to examine their potential effect on cancer in large scale genetic case-control studies involving 10s of thousands of people.

Do antidiabetes medications prevent secondary spread of lung and breast cancer to the brain?

Contact: Kathreena Kurian

Context: Evidence from in vivo and observational studies suggests anti-hyperlipidaemia and -diabetes medications (fibrates and glitazones respectively) may have a role in primary prevention and progression of brain tumours by targeting PPAR-α and -γ, respectively. Howver, whether these agents can prevent the spread of cancers of the lung or breast to the brain is unclear. The aim of this project is to use naturally occurring variation in genes encoding the proteins targeted by drugs to be used as proxies for these targets to examine their potential effect on cancer in large scale genetic case-control studies involving 10s of thousands of people.

pEMT: role in phenotypic plasticity and dormancy

Contact: Abdelkader Essafi

My lab focuses on the timing of and the mechanism underlying embryonic programmes reactivation in cancer using patient specimens, preclinical in vitro and in vivo models, combined with genetic perturbations, state-of-the art sequencing and computational analyses methodologies.

The reason for this focus is two-fold:

1. First, early dissemination/metastasis, therapy resistance, relapse and minimal residual disease, in breast and pancreatic cancers are all caused by increased phenotypic plasticity i.e., the generation of many types of embryonic-like stem cells (SCs) via partial epithelial-mesenchymal transition (pEMT) e.g., therapy tolerant SCs & metastasis-initiating cells (MICs) as well as angiogenic, dormant and persister SCs.
2. Second, the transcriptional and epigenetic mechanisms governing pEMT to reactivate embryonic phenotypic plasticity remain unexplored.

Our projects will delineate the role of the following in the generation and maintenance of the different SCs: 1) stemness and pEMT regulators such as WT1 and LSD1, & 2) epigenetic and metabolic reprogramming downstream of the RNA and DNA targets of these transcriptional regulators.

The work will not only inform prevention, timely diagnosis and therapy but will also give insights into whether as we age: therapy resistance, dormancy and metastasis are epigenetically stabilised pre- or post-therapy and -dissemination.

Contact: Bethan Lloyd-Lewis  

Context: Mammary gland (breast) development is driven by distinct lineage-restricted mammary progenitor cells. These committed progenitors are highly plastic, and are able to change their fate in regenerative contexts. However, the mechanisms underlying mammary epithelial plasticity remain unclear. In this project, we will combine in vivo genetic lineage-tracing with live-cell imaging of mouse tissues in vivo, and mammary organoids ex vivo, to investigate the hypothesis that abnormal cell-cell and cell-matrix interactions underlie mammary epithelial plasticity in response to damage. As cellular plasticity represents an early event in some breast cancers, insights gained during this project will contribute to our understanding of breast tumour initiation.

Contact: Emma Vincent, Rebecca Richmond and/or Mark Gormley.  

Context: Our work indicates that inhibiting PCSK9may increase a person’s risk of head and neck cancer. This effect appears to be independent of the role of PCSK9 inhibition in lowering circulating levels of lipid in the blood. The canonical role of PCSK9 involves binding to and inhibiting the LDL receptor in the liver by promoting its lysosomal degradation. However, relatively little is known about the role of PCSK9 in cancer and almost nothing about how it might act in head and neck cancer. This project therefore aims to investigate the role of PCSK9 in head and neck cancer and to establish how its inhibition might increase risk of this disease. This interdisciplinary project will combine techniques in genetic epidemiology and laboratory-based cancer cell biology.

Contact: Emma Vincent 

Context: The prevalence of obesity has reached epidemic proportions. Recent studies have shown that obesity causes several cancers including colorectal cancer. Because strategies focusing on weight loss and healthier eating habits have failed in populations to deliver sustainable reductions in obesity, we must explore ways to uncouple obesity from cancer. In order to intervene effectively, the biological changes resulting from obesity must be identified and their role in the earliest stages of tumour development understood. Cellular metabolic reprogramming is essential for tumour development as it provide the energy and building blocks required to support chronic cell proliferation. This project will explore the changes to metabolism in the normal colon induced by exposure to insulin (elevated in obese, insulin resistant individuals) to determine the role of insulin in driving colorectal cancer development.   

Contact: Anne Ridley

Once cancers have spread from their site of origin to other sites in the body they are difficult to treat. Using RNAi screens, we have identified genes that are important for different steps of metastasis, including cancer cell migration, invasion, and exit from blood vessels. This project will use a combination of RNAi, small molecule inhibitors, timelapse microscopy and biochemical analysis to test how some of these genes affect cancer progression.

This project seeks to identify targetable tumour vulnerabilities by studying tumour intrinsic and extrinsic properties.

Our laboratory is interested in understanding how tumours support oncogenic properties by deregulating key cellular pathways. By applying classic and cutting-edge techniques on preclinical cancer models and patient specimens, we have previously identified such deregulations in clinically aggressive cancers. Using emerging experimental drugs, we have also succeeded in targeting these mechanisms potently and selectively in cancer cells, highlighting the value of mechanism-directed drug development. This project will focus on exploiting targetable components of the cancer cell cycle. We will also consider associated impacts of the tumour microenvironment on treatment response.

Contact: Siang Boon Koh