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


Project Description

Background

“Warburg metabolism” is characterised by an increased uptake of glucose and its conversion to lactate by glycolysis under normoxia. It is an important feature of cells under physiological/pathological stress such as immune cell activation during inflammation or cancer metabolism; moreover glycolysis is a characteristic of undifferentiated stem cells. 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 pre-neoplastic cell progression. We hypothesized that Warburg metabolism or 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. My lab has developed a tamoxifen-inducible system whereby fluorescent labeled PNCs can be induced in skin tissue with precise temporal control and their interaction with host tissues followed by live imaging. Using this model we have been monitoring PNC and innate immune cell interactions in vivo in real time. We have shown that innate immune cells promote PNC growth during tumour initiation and factors within the PNC developing niche recruit and modulate innate immune cell function. Our preliminary study showed that mitochondria undergo extensive fission in PNCs and the Seahorse Analyzer® analysis showed impaired mitochondrial respiration as well as enhanced glycolysis in PNCs. Thus PNCs undergo a rapid metabolic adaption during their initiation, however we do not know to what extent this is happening.

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.

Aims

Aim 1 Characterize metabolic alteration within the PNC niche

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 of the PNC niche, that generated in the lab to identify altered metabolic pathways and metabolites in the PNC niche.

Aim 2 Using genetic and pharmacological tools to manipulate metabolic pathways in zebrafish larvae

Having characterized metabolic alterations in Aim 1, we will use a newly established lineage specific Cas9 gene inactivation system to alter metabolism in PNCs and examine its impact on PNC growth. We will also use available small molecule agonists or antagonists toward candidate metabolic enzymes to test their impact on PNC growth and survival.

Aim 3 Evaluate the metabolic changes in pre-neoplastic lesions from human patients

Having identified a panel of key candidate genes that contribute to altered metabolism in the PNC niche. We will evaluate their expression changes 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 2020

Qualifications criteria: Applicants applying for a 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.
Residence criteria: The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £15,009 (RCUK rate 2019/20) for UK and EU nationals that meet all required eligibility criteria.

Full eligibility details are available: View Website

Enquiries regarding programme:

References

1. 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.

2. 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

3. 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

4. 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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