MRC DiMeN Doctoral Training Partnership: circRNAs: developing novel biomarkers for Hepatocellular Carcinoma

Background:

Hepatocellular carcinoma (HCC) is one of the most common malignant tumours and the second highest cause of cancer-related deaths worldwide. Five-year survival for newly diagnosed HCC is just 12%, regardless of disease stage, changing little in the past 20 years. Therefore there is an urgent need for better screening, diagnosis, and treatment strategies to improve HCC prognosis. Sensitive biomarkers enabling early HCC surveillance are lacking, as are prognostic biomarkers to predict immunotherapy treatment outcomes in advanced HCC. Circular RNAs (circRNAs) are an emerging species of non-coding RNA holding great potential as diagnostic and prognostic biomarkers for HCC due to their abundance, stability, and high specificity in serum, plasma, and other body fluids.

Objectives:

This project will identify dysregulated circRNAs as novel non-invasive and blood-based biomarkers in HCC diagnosis and prognosis. Dysregulated circRNAs will be identified from HCC FFPE tissue compared to corresponding background liver FFPE from the same patients. Furthermore, to identify circRNAs with potential as unique predictive markers in response to treatment, we will compare baseline samples prior to and during immunotherapy treatment. Finally, we will elucidate the role of altered circRNAs in HCC development and progression.

Novelty:

CircRNAs are an emerging ncRNA species implicated in the regulation of gene expression. Molecular crosstalk between circRNAs and other ncRNA species pervade and define the correct functioning of canonical protein-coding pathways involved in many cellular processes, consequently dysregulation of these networks is implicated in a wide range of cancers. As such the novel properties and dysregulation of circRNAs holds great promise for their utilisation as novel biomarkers.

Timeliness:

Development of applied NGS-based technologies now allows the identification of dysregulated ci circRNAs in cancerous versus non-malignant tissue. These dysregulated circRNAs in HCC are potential prognostic or diagnostic biomarkers and may have future potential applications in RNA-targeting therapeutics.

Experimental Approach:

• NGS-based approaches (CircSeq) established in the primary supervisor’s laboratory will identify dysregulated circRNAs in primary HCC and non-malignant liver samples (obtained by the secondary supervisor).
• Dyregulated circRNAs will then be assessed for abundance, stability, and high specificity in serum, plasma, and other body fluids. Prioritised circRNAs will then be assessed for baseline samples prior to and during immunotherapy treatment.
• The roles of these dysregulated circRNAs will be examined in HCC proliferation and growth using depletion/overexpression studies.

More information on Whitehouse and Samson laboratories are provided here:

https://biologicalsciences.leeds.ac.uk/molecular-and-cellular-biology/staff/156/professor-ade-whitehouse

https://medicinehealth.leeds.ac.uk/medicine/staff/735/dr-adel-samson

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog

Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/how-to-apply