Publications

Cholesterol auxotrophy as a targetable vulnerability in clear cell renal cell carcinoma

A serendipitous meeting at a conference initiated an interdisciplinary collaboration leading to this publication in Cancer Discovery. Dr Emma Vincent and Dr Caroline Bull were interested in the link between lipid metabolites and renal cell carcinoma, a type of kidney cancer. They had found that higher circulating levels of high-density lipoprotein (HDL) cholesterol in the blood was associated with the disease. These data were generated using a technique in genetic epidemiology called Mendelian randomization, which utilises large genetic data sets from populations. Dr Celeste Simon from the University of Pennsylvania happened to visit Emma and Caroline’s poster at the Keystone Tumour Metabolism Conference and revealed she had made a similar observation but using a completely different research discipline. Celeste’s group had used laboratory-based methods in cancer cell biology to discover that renal cell carcinoma cells were dependent on taking up HDL cholesterol for their growth and survival, implicating the HDL receptor as a novel therapeutic target for treating kidney cancer.

This paper is a great example of how the disciplines of genetic epidemiology and cancer cell biology can complement each other. The methodologies are very different, yet the results support each other extremely well. Taking this interdisciplinary approach to writing the paper appealed to the journal and the reviewers and gives strength to the conclusions.

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Supported grant applications

• Dr Helen Weavers (School of Biochemistry) and Professor Paul Martin (School of Biochemistry and School of Physiology, Pharmacology & Neuroscience) applied for (and were successfully awarded) a MRC Programme Grant in 2020 to explore "the mechanisms regulating immune cell extravasation out of vessels in response to injury". Helen said "our proposed study integrates experimental studies, particularly in Drosophila and mice (in collaboration with Prof Sussan Nourshargh at QMUL, a collaborator on the grant), with Population Health approaches, to provide novel mechanistic insight at the molecular and cellular levels as well as the relevance to human health. We approached Dr Ruth Mitchell (EBI Mechanisms to Populations strand Senior Research Associate) during the planning stages of our application and Ruth was able to provide invaluable help in generating some exciting pilot data linking our main gene of interest (a GPCR) to relevant inflammatory diseases (using a variety of genetic epidemiology resources). We believe that this pilot data, together with the advice Ruth offered on writing the Population Health aspects of our grant, was a key factor in our grant’s success."
• Dr Caroline Bull (School of Cellular and Molecular Medicine) applied for (and was successfully awarded) a University Cancer Research Fund grant for her project "Formulating cell culture media to reflect the metabolic environments of obesity and type 2 diabetes: preclinical models educated by population data."Cell culture media encompasses a broad variety of reagents designed to support the maintenance of cells in vitro. Even though nutrient concentrations in standard media poorly resemble human plasma, most studies examine cells maintained in these media. This has implications for the translation of preclinical findings, as it is known that cellular metabolic networks are flexible and influenced by nutrient availability. Obesity and type 2 diabetes are established risk factors for cancer, and it is thought that the metabolic environment in these conditions contribute to cancer development. We have received support from the University Cancer research fund to develop formulas for cell culture media that reflect the metabolic environments of obesity and type 2 diabetes, using a genetic epidemiological technique called Mendelian randomization. We hypothesize that culturing cells in these modified media may reveal distinct cell behaviours which contribute to cancer risk at the population level.

Fostering collaborations 

Professor Celia Gregson (Bristol Medical School) and Dr Chrissy Hammond (School of Physiology, Pharmacology & Neuroscience)

Celia said "Chrissy and I share a symbiotic interest in bone and joint genetics, my perspective is human and hers the Zebrafish. We’ve collaborated since 2013, and over the years, and across our faculties, we have managed to bridge the inter-disciplinary gap, understand our different scientific perspectives, and help others to do so too. We were first able to support Dr Ben Faber to secure an EBI Clinical Primer to begin to study osteoarthritis genetics (2015) - he went on to be awarded a MRC Clinical PhD fellowship to pursue this further. Following his PhD, Dr Dylan Bergen was awarded an EBI discipline hopping fellowship (2017) to spend time in the musculoskeletal research unit, learning population genetics to enrich his laboratory-based PhD work. On this basis he successfully secured a Versus Arthritis post-doc fellowship with us both. Most recently, Dr Neelam Hassan was awarded an EBI Clinical Primer (2020) laying the foundation for her subsequent MRC Clinical PhD fellowship to study high bone mass genetics, combining both population genetic and Zebrafish research. Chrissy and I have been able to co-publish human genetic discoveries, with complementary functional Zebrafish experiments to achieve higher impact. We work together, holding quarterly interdisciplinary group meetings, and providing clinical/ laboratory perspectives to PhD students, aiming to maximise translational potential. It’s also just really interesting to learn about another field!"

 PhD Studentships

Lucy Goudswaard (School of Physiology, Pharmacology and Neuroscience) is a PhD student on the British Heart Foundation Integrative Cardiovascular Programme. "My PhD project uses a combination of lab work, clinical studies and epidemiology. The aim of my project is to determine how obesity causes cardiovascular disease by focusing on changes in platelets, the key cells involved in forming clots. I also use proteomic data to explore whether changes in circulating proteins might increase cardiovascular risk. I have really enjoyed the multidisciplinary aspect – it has provided a range of opportunities from designing and carrying out my own clinical study to doing an epidemiological placement at the Wellcome Sanger Institute in Cambridge."