Dimitrios Anastasiou

 

The role of hepatic cell metabolism in liver regeneration and liver cancer

In the last two 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]. 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. 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 metabolic changes in specific hepatic cell populations contribute to liver disease and HCC development.

The liver has a remarkable capacity to regenerate after injury [2], but failure in this regeneration process is thought to lead to cancer [3]. To preserve its important physiological functions in the mammalian body, the liver undergoes significant metabolic adaptations after damage and during tumorigenesis. The Anastasiou Lab are studying, among other topics, how whole-body and liver metabolism adapt during the development of HCC and after chemical or mechanical damage, as models of the regenerative processes that occur during liver disease. In recent unpublished work, we have found changes in carbohydrate and lipid metabolism occurring during mouse liver regeneration that are similar, at the level of the whole tissue, to those seen in livers with HCC. We have also shown that these changes are driven, in part, by metabolic reprogramming in hepatic non-parenchymal (NP) cells, which have many essential signalling functions for both regeneration and cancer. However, how metabolic adaption of NP cell metabolism influences liver homeostasis is unclear.

In this project, we will address this question using mouse genetics to interfere with metabolic pathways that we found altered in NP cells during liver regeneration and cancer. We will then use in vivo and ex vivo metabolic measurements to understand the consequences of these genetic manipulations in normal liver function as well as during regeneration and HCC development. To this end, the student will combine stable isotope tracers in cultured cells and in mice, with nuclear magnetic resonance (NMR) and mass spectrometry (MS) metabolomics. The student will also use flow cytometry to isolate and characterise hepatic NP cell populations. In addition to uncovering fundamental physiological functions of hepatic NP cell metabolism in mammals, this project will also provide important insights towards targeting NP cell metabolism for cancer therapy [4].

1. The Lancet Commission. (2014). 'UK liver disease crisis.' from http://www.thelancet.com/pb/assets/raw/Lancet/stories/commissions/lancet-liver-disease-infographic.pdf.

2. Karin, M. and Clevers, H. (2016)
Reparative inflammation takes charge of tissue regeneration.
Nature 529: 307-315. PubMed abstract

3. Sun, B. and Karin, M. (2012)
Obesity, inflammation, and liver cancer.
Journal of Hepatology 56: 704-713. PubMed abstract

4. Anastasiou, D. (2017)
Tumour microenvironment factors shaping the cancer metabolism landscape.
British Journal of Cancer 116: 277-286. PubMed abstract