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MRC DiMeN Doctoral Training Partnership: Novel breast cancer theranostics: utilising advanced sodium MRI to track response to therapy


   MRC DiMeN Doctoral Training Partnership

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  Dr W Brackenbury, Dr A Kennerley, Dr M Muthana  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

York United Kingdom Biochemistry Biomedical Engineering Biophysics Cancer Biology Cell Biology Developmental Biology Immunology Molecular Biology Pharmacology Physiology

About the Project

Approximately 1000 women die of breast cancer every month in the UK and there is a need for better imaging biomarkers for detection and monitoring treatment response. Existing approaches have limited sensitivity or use hazardous radioactive probes. We recently discovered using non-invasive sodium imaging (23Na-MRI) that sodium is elevated in breast cancers in mice. Importantly, sodium is better for detecting tumours than standard MRI. Excitingly, the sodium level is reduced in response to chemotherapy, demonstrating enormous predictive benefits over existing technology. These findings underscore the importance of sodium as an informative, yet unutilised biomarker. In this project, you will build on these findings and explore how sodium responds to different classes of breast cancer therapy, including hormone therapy, radiotherapy and immunotherapy, with a specific focus on understanding what metabolic and physiological changes in tumours accompany the sodium changes.

We will use a range of sophisticated in vivo and in vitro breast cancer models, including 3D spheroids, as well as xenograft and allograft mouse models, to evaluate how tumour sodium responds to different classes of therapy. Importantly, we will use multi-parametric MRI (e.g. blood oxygenation, diffusion, chemical exchange, magnetisation transfer) to understand what metabolic and physiological changes in tumours accompany altered sodium. We will also undertake metabolomic profiling of tumours responding to therapy. We will modulate expression of specific targets responsible for sodium handling (e.g. ion channels) using pharmacological and genetic (RNAi, CRISPR) techniques. We will measure channel activity using a combination of electrophysiology (whole cell patch clamp recording) and ion-sensitive dyes. We will also study the effects on downstream signalling and cellular behaviour using molecular cell biology approaches. The project will therefore expose the student to a range of cutting-edge in vivo imaging and cell biology techniques in labs in York and Sheffield that are leading in this field. As sodium plays a key role in normal cellular physiology and in several diseases, this project is expected to provide novel mechanistic insights into an important, and relatively understudied signalling mechanism.

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: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards

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

http://www.dimen.org.uk/how-to-apply/application-overview


Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover UK tuition fees, stipend and project costs as standard. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of bursaries that will enable full studentships to be awarded to international applicants. These full studentships will be awarded to exceptional candidates only, due to the competitive nature of this scheme. Please read additional guidance here: http://www.dimen.org.uk/how-to-apply/eligibility-funding
Studentships commence: 1st October 2022
Good luck!

References

1. James AD, Leslie TK, Kaggie JD, Wiggins L, Patten L, O’Duinn JM, Langer S, Labarthe MC, Riemer F, Baxter G, McLean MA, Gilbert FJ, Kennerley AJ & Brackenbury WJ. (2021). Sodium accumulation in breast cancer predicts malignancy and treatment response. bioRxiv 2021.04.14.439494. https://www.biorxiv.org/content/10.1101/2021.04.14.439494v1
2. Leslie TK, James AD, Zaccagna F, Grist JT, Deen S, Kennerley A, Riemer F, Kaggie JD, Gallagher FA, Gilbert FJ & Brackenbury WJ. (2019). Sodium homeostasis in the tumour microenvironment. Biochim Biophys Acta Rev Cancer 1872, 188304. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115894/
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