FULLY FUNDED PROJECT - Targeting mitochondria to stall the engine in liver cancer

   College of Medical, Veterinary and Life Sciences

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  Dr Tom MacVicar, Prof Tom Bird  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

'To apply, please click institution web link'*

Aberrant metabolism plays a central role during the development of liver cancer through diseases including NAFLD/NASH. Targeting metabolic pathways has emerged as a potential route to improve poor responses to standard therapy of hepatocellular carcinoma (HCC). Mitochondria provide cancer cells with remarkable metabolic flexibility and plasticity. Mitochondria reprogram cellular metabolism to drive tumour growth and adaptation to the microenvironment as well as support tumour resistance to chemotherapy; including immunotherapy. For instance, dysregulation of the metabolic master regulator mTORC1, which is an important feature in HCC driven by hyperactive Wnt signalling, rewires the mitochondrial proteome to facilitate cancer cell adaptation to glutamine deprivation and hypoxia (MacVicar et al., 2019). However, it remains unclear how mitochondria are regulated in liver tumours and how this varies across the spectrum of heterogeneous HCC disease.

Mitochondria require nucleotide building blocks for the expression of respiratory chain proteins encoded by the mitochondrial genome. Exciting preliminary data indicates that mitochondrial nucleotide supply and mitochondrial DNA expression is limiting for liver cancer cell growth. Furthermore, disturbed mitochondrial nucleotide metabolism has been shown in vitro to trigger innate immune responses, which may impact the response of tumours to nucleoside analogue therapy (Sprenger et al., 2021). Pioneering work by Tom Bird’s laboratory has established a suite of genetically-engineered in vivo and in vitro models that faithfully represent heterogenous cases of human HCC (Mueller et al., 2022). Intriguingly, transcriptomic data indicate that mitochondrial activity and associated metabolic pathways vary depending on the mutational status of the cancer.

The student will utilise this new resource to investigate the importance of mitochondrial nucleotide metabolism across different subtypes of HCC. The student will test whether blocking mitochondrial nucleotide supply is a viable therapeutic option in HCC by first screening a panel of HCC organoids derived from different genetic mouse models, including integration with organoid/tissue from the CRUK Scotland Centre, before selecting pre-clinical models to target in vivo. In addition to specifically targeting mitochondrial nucleotide metabolism, the student will take a complimentary approach to explore mitochondrial function and biogenesis in a spatial manner within different subtypes of HCC. Proteomic analysis of human HCC indicates that mitochondria are reprogrammed in liver tumours with some striking outcomes, including an upregulation of proline synthesis enzymes and accumulation of machinery involved in the expression of mitochondrial DNA (Jiang et al., 2019). However, it is unclear from such bulk tissue analysis to what degree mitochondrial reprogramming occurs in the cancer cells themselves or how mitochondrial regulation varies across the spectrum of HCC diseases. In collaboration with the Histopathology and Deep Phenotyping team at the Beatson Institute, the student will perform multispectral imaging of mitochondrial proteins and transcripts to spatially explore mitochondrial reprogramming within different HCC tumour microenvironments including those undergoing hypoxia and dysregulated mTORC1 activity.

Overall, this research project will expand our understanding of mitochondrial function in liver cancer and directly test the potential of targeting mitochondrial nucleotide metabolism as a precision medicine approach to tackle difficult to treat subtypes of HCC.

Entry requirements: candidates should hold at least an upper second-class degree in a relevant subject and comply with University of Glasgow English Language requirements.

*You must download and complete the below form with your application.

CRUK_Scotland_Centre_recruitment form.docx

Biological Sciences (4)

Funding Notes

Applications are open to all individuals.
PhD studentship available to start in October 2023 for an outstanding applicant with a stipend of £21,000 p/a. This will be funded by the CRUK Scotland Centre, a joint initiative between the University of Edinburgh and the University of Glasgow.
Please note that applicants are not required to submit a research proposal when completing the online application. The CRUK EDI form is required for the process of application. please complete and upload on the Applicant Self-Service Portal.
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