Using functional genomics to dissect mutant-clone selection in the early stages of liver cancer development

Dr Alexander Raven, University of Glasgow & Dr Luke Boulter, University of Edinburgh

Background

There is a clinical need to improve detection and therapeutic intervention in hepatocellular carcinoma (HCC). Preferably both goals should be targeted at the early stages of disease to maximise successful clinical outcomes. It is therefore essential that we study hepatocyte clonal dynamics to better understand how oncogenic-mutant-clones expand and progress to cancerous lesions.

The PhD project aims to identify the key signalling pathways that promote oncogenic growth and selection of pro-cancerous clones. Using an in situ CRISPR/Cas9 screen, the project will combine clonal barcoding with functional genomics. Enabling the identification of key plasma membrane receptors that stimulate the growth of mutant-clones in a pre-cancerous, diseased tissue environment. HCC is strongly linked to social deprivation and the associated poor diet that occurs in that setting. To encompass this feature into the disease model the project will also include the use of a high fat and sugar diet to simulate tumourigenesis in an inflamed and steatotic liver.

By focusing the screen on genes that encode cell surface proteins the project aims to identify targets that are pharmacologically accessible and have greater potential for therapeutic translation. To further accelerate translation of the screening results to the clinic, gene hits will be prioritised by aligning them to patient single cell and spatial transcriptomic data sets. This will ensure identified genes and pathways are specific to human HCC. Further emphasis will be placed on the availability of small molecule inhibitors or other therapeutic agents that can target key hits. Follow up work using in vitro assays and in vivo preclinical models of HCC will validate gene hits and explore methods to target them in the clinic. Working closely with the clinicians in the CRUK Scotland Centre out comes from this project will direct new strategies in the detection and treatment of HCC.

Skils/Techniques that will be gained

Techniques/model systems

Pre-clinical modelling of disease using genetically engineered mouse models.

Spatial and single cell transcriptomic assays and analysis

In vivo gene editing using CRISPR/Cas9 technology

Ex vivo tissue slice culture

Cancer organoid lines

Training

Specific laboratory training for the techniques listed above in addition to bioinformatic and computational training for analysis of large data sets. Furthermore, the University of Glasgow post-graduate research programme and the CRUK Scotland Centre doctoral training programme both provide excellent training in more generic research skills such as scientific writing and communication and public engagement. The PhD candidate will also have access to mentoring schemes and career support to build their network and explore various career paths

For further information on the project or informal enquiries, please contact Dr Alexander Raven, This email address is being protected from spambots. You need JavaScript enabled to view it.

When submitting your application please also upload the completed EDI recruitment form.

To place an application, please visit this site at the University of Glasgow. Please note that due to funding requirements this opportunity is open to UK applicants only.