Mechanisms and functions of host metabolic reprogramming in liver cancer development

A PhD project for the 2022 doctoral clinical fellows programme with Dimitrios Anastasiou (primary supervisor, Crick) and Emmanouil Tsochatzis (UCL)

Project description

In 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].

Emmanouil Tsochatzis

Professor of Hepatology, UCL

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 therapies. It is unclear what causes progression from liver disease to HCC but stopping this transition would halt the imminent increase in HCC incidence. This project will use mouse models to understand how systemic metabolic changes in the host, mediated by specific hepatic cell populations, contribute to HCC development.

The Anastasiou Lab are studying, among other topics, how whole-body and liver metabolism co-adapt to obesogenic diets and during the development of 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. In recent unpublished work, using in vivo metabolic imaging and ex vivo metabolomic analyses, we have shown that HCC induces characteristic changes in carbohydrate and lipid metabolism in the peritumoral liver. Using immunodeficient mice, we have also shown that HCC-induced host metabolic changes require a functioning immune system, which has important roles in tumorigenesis and response to therapy [3,4].

In this project, the successful candidate will study how HCC influences the composition of peritumoral immune cell populations; we will then investigate the role of the altered immune environment in HCC-induced host metabolic reprogramming. To this end, we will use flow cytometry and mass cytometry (CyTOF) to characterise immune cells in mouse models of HCC, and mouse genetics to interfere with metabolic pathways in hepatocytes and the function of immune cells to study their impact upon HCC development. These approaches will be complemented by nuclear magnetic resonance (NMR) and mass spectrometry (MS) metabolomics combined with stable isotope tracers in cultured cells and in mice. In addition to uncovering fundamental principles of metabolic homeostasis, this project will also provide important insights towards targeting both HCC and host metabolism for cancer therapy.

The partner institution for this project is UCL.

References

  1. http://www.thelancet.com/pb/assets/raw/Lancet/stories/commissions/lancet-liver-disease-infographic.pdf
  2. Kim, E. and Viatour, P. (2020). Hepatocellular carcinoma: old friends and new tricks. Exp Mol Med 52: 1898-1907.
  3. Anastasiou, D. (2017). Tumour microenvironment factors shaping the cancer metabolism landscape. Br J Cancer 116: 277-286.
  4. Hiam-Galvez, K. J., Allen, B. M. and Spitzer, M. H. (2021). Systemic immunity in cancer. Nat Rev Cancer 21: 345-359.