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MRC DiMeN Doctoral Training Partnership: Targeting ageing mitochondrial metabolism with dietary interventions to combat colorectal cancer


Project Description

Background
Colorectal cancer is the second most common cause of death by cancer in the UK. Diet in particular, impacts on colorectal cancer development. However the precise nature of which specific components of the diet promote cancer growth have remained elusive. Recently, we found that mutations in the mitochondrial DNA (mtDNA) that accumulate during ageing accelerate colorectal cancer growth in humans and mice. Furthermore, these mtDNA mutations cause a set of specific metabolic changes, that we hypothesise drive tumour cell proliferation. Targeting these specific metabolic changes using dietary interventions is therefore an extremely promising treatment strategy. Only when the precise metabolic requirements of cancer cells are known, can dietary interventions be translated to the clinic. This is the mechanistic challenge we would like you (the student) to tackle.

Approach
The interactions between mtDNA mutations, metabolism and cancer are multimodal, which means that a comprehensive study will require substantial sample sizes. We therefore propose to use a model we have recently developed, the first Drosophila melagonaster (fly) model of metastatic colorectal cancer. Our fly model allows the measurement of growth of the primary tumour, as well as of metastases (GFP & luciferase labelled), and we have recently established in this model that dietary restriction increases survival. This model now provides the unique opportunity to comprehensively investigate the effects of mtDNA mutations, diet and cellular metabolism on tumour growth, using large high-throughput experiments.

The fly, an experimental genetics powerhouse, allows the manipulation and measurement of mtDNA mutation load, the insertion of specific mitochondrial genomes and the assessment of the metabolic signature in both cancer and somatic cells. Additionally, we can make efficient and highly precise dietary manipulations. This will allow you to discover, and subsequently modulate, novel molecular targets. In addition, from our previous work we have already identified candidate mechanisms and associated diets for you to focus on.

Techniques used
Mass spectrometry to assess metabolic profile. High-resolution imaging and cell sorting. MtDNA sequencing. Transcriptomics (RNAseq) and proteomics (TMT Mass spec). Diet manipulations and longevity measurements. CRISPR/RNAi/Drug screening where required and functional genetics to test key mechanisms/therapies.

Training / Research environment
Your supervisor team consists of three highly successful research group leaders with complimentary experience. You will join a thriving community with outstanding peer support and training opportunities. You will spend time between our three labs and will be encouraged to shape your own PhD project. Importantly, you will receive high-quality training tailored to your needs and interests including internationally renowned courses.

This PhD project will train you to become an interdisciplinary quantitative scientist with experience in whole organism biology. In the fly, the best of functional genetics is but a cross away, and data is generated fast. This allows you to make mistakes and learn from them without causing delays. Quantitative skills are key to modern life sciences and we use various state-of-the-art statistics and bioinformatics that you will gain hands-on experience with. The proposed project is inherently interdisciplinary crossing boundaries between nutrition, ageing, mitochondrial biology, metabolism and cancer.

Supervisor information
Mirre J P Simons, Sir Henry Dale Fellow, Animal & Plant Sciences, Bateson Centre, University of Sheffield
@MirreSimons
http://www.simons-lab.group.shef.ac.uk

Kyra Campbell, Sir Henry Dale Fellow, Biomedical Science, Bateson Centre, University of Sheffield
cellplasticity.weebly.com
@KyraCampbellLab

Laura Greaves, Wellcome Centre for Mitochondrial Research, University Research Fellow, University of Newcastle
https://www.newcastle-mitochondria.com/laura-greaves/
@LauraGreaves81

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 can be found on our website:
http://www.dimen.org.uk/

Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Includes:
Stipend at national UKRI standard rate
Tuition fees
Research training and support grant (RTSG)
Travel allowance
Studentships commence: 1st October 2020.

To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website

Good luck!

References

Greaves, L. C. et al. Clonal Expansion of Early to Mid-Life Mitochondrial DNA Point Mutations Drives Mitochondrial Dysfunction during Human Ageing. PLoS Genet. 10, e1004620 (2014).

Campbell, K. et al. Collective cell migration and metastases induced by an epithelial-to-mesenchymal transition in Drosophila intestinal tumors. Nat. Commun. 10, 2311 (2019).

Garratt, M., Nakagawa, S. & Simons, M. J. P. Comparative idiosyncrasies in life extension by reduced mTOR signalling and its distinctiveness from dietary restriction. Aging Cell 15, 737–743 (2016).

How good is research at University of Sheffield in Biological Sciences?

FTE Category A staff submitted: 44.90

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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