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Precision Medicine DTP - Investigating the metabolic alterations that initiate pre-neoplastic development in zebrafish and in humans


College of Medicine and Veterinary Medicine

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Dr Y Feng , Dr K Burgess , Dr R Burchmore , Dr G Ho No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Altered metabolism is one of the hallmarks of cancer. To date, metabolic reprogramming of cancer cells has been recognized as a target for therapeutic intervention. However, it is unclear as to when and how metabolic changes occur during the initiation and progression of pre-neoplastic lesions. It is also unclear how altered metabolism impacts on the progression of a pre-neoplastic lesion. The central hypothesis of the current project is “Metabolic change is an early event during pre-neoplastic cell initiation and plays an important role in supporting pre-neoplastic cell (PNC) progression.” Until recently, it has been difficult to investigate PNC initiation and progression in vivo with precise spatiotemporal information due to limitations of available animal models. The Feng lab has developed a tamoxifen-inducible system whereby fluorescent labeled PNCs can be induced in zebrafish larval skin tissue with precise temporal control and their interaction with host tissues followed by live imaging. Using this model our preliminary studies showed that PNC undergo metabolic changes at their inception, and modulating the metabolic environment might lead to their elimination, thus allowing the development of novel cancer prevention strategies.

In the current project we seek first to characterize metabolic changes within the PNC niche, second to identify pathways in PNCs that are important for these metabolic alterations and finally to determine how metabolic alterations contribute to PNC progression. We also want to evaluate whether the changes that we identified also occur in pre-neoplastic human lesions.

The student will perform LC-MS and GC-MS based metabolomics using a zebrafish larval PNC model. Data obtained will be integrated and analyzed systematically with RNAseq and proteomic data for the PNC niche, generated in the lab to identify altered metabolic pathways and metabolites in the PNC niche.

The student will also employ both lineage specific the Cas9 gene inactivation system to alter metabolism in PNCs and examine its impact on PNC growth, and will also use available small molecule agonists or antagonists toward candidate metabolic enzymes to test their impact on PNC growth and survival.

Finally, the project will evaluate gene expression changes that are related to metabolic pathways identified in zebrafish model, in a panel of pre-neoplastic lesions in humans (dysplastic colonic polyps, dysplasia-associated mass lesion (DALM) in inflammatory bowel disease and Barrett’s oesophagus.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.

For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2021

Qualifications criteria: Applicants applying for an MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualification, in an appropriate science/technology area. The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £15,285 (UKRI rate 2020/21).

Full eligibility details are available: http://www.mrc.ac.uk/skills-careers/studentships/studentship-guidance/student-eligibility-requirements/

Enquiries regarding programme: [Email Address Removed]

References

- Laux DW, Kelly L, Bravo IR, Ramezani T, Feng Y. Live imaging the earliest host innate immune response to preneoplastic cells using a zebrafish inducible KalTA4-ER(T2)/UAS system. Methods Cell Biol. (2017);138:137-150.
- van den Berg MCW, MacCarthy-Morrogh L, Carter D, Morris J, Ribeiro Bravo I, Feng Y, Martin P. Proteolytic and Opportunistic Breaching of the Basement Membrane Zone by Immune Cells during Tumor Initiation. Cell Rep. (2019) Jun 4;27(10):2837-2846. PMID: 31167131
- Haggarty, J, Oppermann, M., Dalby, MJ, Burchmore, RJ, Cook, K, Weidt, SK, Burgess, K, Serially coupling hydrophobic interaction and reversed-phase chromatography with simultaneous gradients provides greater coverage of the metabolome Metabolomics (2015) 11 (5), 1465-1470
- Akpunarlieva S, Weidt S, Lamasudin D, Naula C, Henderson D, Barrett M, Burgess K, Burchmore R. Integration of proteomics and metabolomics to elucidate metabolic adaptation in Leishmania. J Proteomics. 2017 Feb 23;155:85-98.


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