About the Project
Can nutritional and ageing biology solve the problem of prostate cancer? This project will test this idea using experiments in Drosophila.
Prostate cancer (PCa) accounts for more than a quarter of male cancers in the UK, one third of which occur >75yrs. Environmental risk factors are evidenced by worldwide variation in PCa rates and changes in risk when migrants change countries. Among risk factors, nutrition is of particular importance. At a molecular level, it is thought to be linked to mis-regulated mTOR signalling in the mTORC1 nutrient-sensing pathway.
Unfortunately, there is little clarity on how these mechanisms connect to cause cancer in vivo, limiting progress in the clinic. Nutrition and mTOR are known evolutionarily conserved regulators of ageing and age-related disease, and mTOR plays a role in tumour-promoting exosome production. But whether nutrient/mTOR interventions could prevent or reverse PCa remains unclear. To address this multidimensional problem experimentally, we propose to use the functional genetics powerhouse, the fruit fly (Drosophila melanogaster).
Your PhD’s objectives will be to assay the impacts of age and (1) diet, (2) mTORC1 pathway components using genetic manipulations, and (3) drugs that precisely target components of the mTORC1 pathway, on prostate-like cell growth and genome replication in different prostate growth states (benign, PCa, and castration-resistant prostate cancer [CRPC]).
The fly system allows for rapid tests of diet, genetic and pharmaceutical interventions in a PCa model. The secondary cells (SCs) of male Drosophila share fundamental features with the human prostate: they make seminal fluid and exosomes, and growth is regulated by steroid-dependent and -independent signals, mirroring healthy prostate and CRPC respectively. SC growth and endoreplication will be assayed in (A) males fed diets that vary in carbohydrates, protein, and fats, including compositions known to extend lifespan, (B) males with mutations affecting mTORC1 signalling, focusing on those known to extend lifespan, and males with SC-specific manipulation of mTORC1 signalling, and (C) males treated with lifespan-extending drugs that target mTORC1 pathway components.
The experiments will reveal how nutrient/mTOR effects on the whole-organism influence PCa-relevant cellular activity, which will inform the development of candidate prophylactic nutritional interventions for PCa. By focusing on interventions that modulate ageing the project will test whether anti-ageing therapies have the potential to combat many diseases simultaneously, contributing more broadly to our understanding of the role of nutrition to healthy ageing.
The student will receive training in a wide range of skills including cell imaging techniques; whole organism physiology; in vitro assays; genetics; and statistics.
The interdisciplinary supervisor team has expertise in Drosophila reproduction, pioneering the use of secondary cells as a prostate cancer model; nutrition, ageing and mTOR; and nutritional requirements for tumour development in the fly.
The project will be based primarily in the fly lab at the University of Liverpool. For more information contact a supervisor: lead supervisor Dr Stuart Wigby (@stuartwigby / wigbylab.com); co-supervisors Prof Clive Wilson (https://www.dpag.ox.ac.uk/team/clive-wilson), Dr Mirre Simons (@MirreSimons / https://simons-lab.group.shef.ac.uk/), Dr Daimark Bennet (@daimarkbennett / https://www.liverpool.ac.uk/integrative-biology/staff/daimark-bennett).
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 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:
Studentships commence: 1st October 2021
Sepil, I., Hopkins, B. R., Dean, R., Bath, E., Friedman, S., Swanson, B., Ostridge, H. J., Harper, L., Buehner, N. A., Wolfner, M. F., Konietzny, R., Thézénas, M.-L., Sandham, E., Charles, P. D., Fischer, R., Steinhauer, J., Kessler, B. M., & Wigby, S. (2020). Male reproductive aging arises via multifaceted mating-dependent sperm and seminal proteome declines, but is postponable in Drosophila. Proceedings of the National Academy of Sciences, 117(29), 17094–17103. https://doi.org/10.1073/pnas.2009053117
Fan, S., Kroeger, B., Marie, P. P., Bridges, E. M., Mason, J. D., McCormick, K., Zois, C. E., Sheldon, H., Khalid Alham, N., Johnson, E., Ellis, M., Stefana, M. I., Mendes, C. C., Wainwright, S. M., Cunningham, C., Hamdy, F. C., Morris, J. F., Harris, A. L., Wilson, C., & Goberdhan, D. C. (2020). Glutamine deprivation alters the origin and function of cancer cell exosomes. The EMBO Journal, 39(16), 1–27. https://doi.org/10.15252/embj.2019103009
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