Metabolic rewiring of Hepatocellular Carcinoma

• Professor Alex von Kriegsheim: alex.vonkriegheim@ed.ac.uk
• Dr Rachel Guest: rachel.guest@ed.ac.uk
• Dr Luke Boulter: luke.boulter@ed.ac.uk
• Dr Stephen Chapman: Stephen.Chapman@liverpool.ac.uk

Application deadline

17th October 2025

Funding information (students eligible to apply) - UK/International students

This is a fully funded three-year PhD studentship. The funding covers tuition fees at the UK home rate, an annual tax-free stipend (starting at £20,780 in year one), and a research consumables budget. 

Start date: March 2026.

Applications are open to all, but please note that the funding will only cover tuition fees at the UK rate. International students are welcome to apply, but will need to apply to the University of Edinburgh to cover the difference between the UK and international tuition fees.

Project description

Introduction:

Liver cancer is a significant and growing health concern in Scotland. Over the past two decades, the incidence of liver cancer has doubled, and it now represents a major cause of mortality. Hepatocellular Carcinoma (HCC), the most common type of primary liver cancer, is particularly aggressive and currently lacks effective targeted treatments. This project aims to address this urgent clinical need by investigating the fundamental metabolic changes that drive HCC progression.

Scientific Background:

Lifestyle factors associated with altered metabolism, such as obesity, diabetes, and alcohol consumption, are known risk factors for HCC. These conditions promote a profound shift in how liver cells produce energy. Healthy liver cells are metabolically flexible, primarily using fats (lipids) for energy. However, as cancer develops, tumour cells "rewire" their metabolism to become heavily dependent on glucose metabolism. This project is built on the key discovery that the loss of a liver-specific protein, JMJD5, drives this metabolic switch. Our preliminary data show that when JMJD5 is lost in liver cancer cells, they increase their consumption of glucose and production of fats, mimicking the metabolic state observed in advanced HCC tumours. As JMJD5 is highly expressed in healthy liver tissue but frequently lost during tumour progression, we hypothesise that its absence is a key event that makes cancer cells dependent on specific metabolic pathways, creating a potential vulnerability that can be exploited with targeted drugs.

Project Aims & Methods:

This PhD project will integrate existing data into an In silico metabolic model to analyse metabolic fluxes of HCC to identify these new therapeutic targets. Using state-of-the-art techniques, the student will investigate how the loss of JMJD5 rewires cancer cell metabolism for model validation. The project will utilise a combination of CRISPR gene-editing in liver cancer cell lines, a cutting-edge ex vivo model using precision-cut tissue slices from human HCC tumours and the latest mitochondrial metabolic model for a true systems biology analysis. This unique approach preserves the complex architecture and cellular diversity of the original tumour, providing a highly physiologically relevant system for study.

The student will receive comprehensive training in:

Metabolomics and Isotope Tracing: Using advanced mass spectrometry to trace the fate of nutrients (like ¹³C-glucose and ¹⁵N-glutamine) through metabolic pathways.

Proteomics and Lipidomics: To create a complete map of the proteins and fats within the cancer cells.

Computational Modelling: Integrating the multi-omics data into a predictive computer model of cancer metabolism. This model will be used to identify metabolic "choke points" and potential drug targets.

Ex vivo Tissue Slice Culture: A cutting-edge technique for maintaining live human tumour tissue in the lab.

By combining these experimental and computational approaches, this project will identify the specific metabolic dependencies of HCC cells. The findings will provide a strong rationale for testing novel therapeutic strategies, with the ultimate goal of identifying new, effective treatments for this deadly disease.