Project background and description
Over the last three decades, there has been an alarming increase in the number of patients with liver disease linked to obesity, alcohol consumption, environmental toxins and pathogens [1, 2]. If current epidemiological trends continue, about a fifth of these patients will develop hepatocellular carcinoma (HCC), which has a high mortality rate due to lack of effective therapy options [3]. It is unclear what causes progression from liver disease to HCC but stopping this transition would halt the imminent increase in HCC incidence. In this context, we are seeking a highly motivated student to undertake a project within the broader area of the role played by inter-organ interactions in HCC initiation and development.
A major focus of the Anastasiou Lab is to understand how whole-body and liver metabolism co-adapt after hepatic tissue damage and during transition to HCC. Our ultimate goal is to identify the molecular mechanisms that mediate the transition from liver disease to HCC and design new therapeutic strategies that target these mechanisms. To this end, we study the metabolism of both hepatic tumours and extra-hepatic tissues in various diet-, chemically- and genetically-induced mouse models of liver disease and cancer. In recent unpublished work, we have identified distinct changes in carbohydrate and lipid metabolism that occur at the whole-body level and precede or coincide with the development of HCC. In collaboration with mathematical biologists, we have generated an array of metabolic network models [4] of various tissues during different stages of HCC development. Intriguingly, these models reveal co-ordinate changes in the metabolism of the liver and extra-hepatic tissues and have identified candidate metabolic, signalling and transcription pathways that mediate inter-organ cross talk.
Potential projects in this area, to be agreed together with the successful candidate, include, but are not limited to (a) assessing the contribution of extra-hepatic tissue metabolism in the development of HCC, (b) investigating the role of immune cells in systemic metabolic changes associated with HCC and (c) testing the functions of candidate signalling mechanisms in inter-organ metabolic communication. By the end of the project, in addition to core laboratory techniques (molecular and cell biology, protein biochemistry) the student will be proficient in nuclear magnetic resonance (NMR) and mass spectrometry (MS)-based metabolomics (tissue processing, metabolite extraction, sample analysis, data acquisition and statistical analysis), the use of stable isotope tracers for analysis of mouse liver metabolism and methods to study whole-body physiology.
Candidate background
This project would be particularly suitable for candidates with excellent quantitative aptitude and a background in chemistry, biochemistry, metabolism, and animal physiology. The candidate should also have a strong interest in working with mouse models of cancer. Although not a pre-requisite, knowledge in computational programming (R, MATLAB, Python) would be desirable.
References
1. The Lancet Commission (2014)
"UK Liver Disease Crisis" infographic.
Available at: https://www.thelancet.com/pb/assets/raw/Lancet/stories/commissions/lancet-liver-disease-infographic.pdf
2. Yang, J.D., Hainaut, P., Gores, G.J., Amadou, A., Plymoth, A. and Roberts, L.R. (2019)
A global view of hepatocellular carcinoma: trends, risk, prevention and management.
Nature Reviews Gastroenterology & Hepatology 16: 589-604. PubMed abstract
3. Bruix, J., da Fonseca, L.G. and Reig, M. (2019)
Insights into the success and failure of systemic therapy for hepatocellular carcinoma.
Nature Reviews Gastroenterology & Hepatology 16: 617-630. PubMed abstract
4. Mardinoglu, A., Boren, J., Smith, U., Uhlen, M. and Nielsen, J. (2018)
Systems biology in hepatology: approaches and applications.
Nature Reviews Gastroenterology & Hepatology 15: 365-377. PubMed abstract
