MRC PhD Studentship 2010 – (4 years)
‘Metabolic Status Modulates Tumour Cell Sensitivity to Apoptotic Stimuli: Development ofNovel Strategies to Enhance Tumour Cell Death’
Supervisors: Dr Kelvin Cain and Dr Marion MacFarlane
Aims:
1) To determine how the metabolic status of the cell can modulate sensitivity to receptor (extrinsic) and chemical-induced (intrinsic) stimuli.
2) To determine how modulation of tumour cell metabolism can induce changes in various signalling pathways that induce/regulate tumour cell survival/killing.
3) To use this fundamental understanding of the relationship between cell death and energy metabolism to develop different therapeutic approaches to enhance tumour cell killing.
Background:
Tumours often re-programme their metabolism to ensure constant ATP supplies, reducing equivalents and metabolites for growth. The classical view is that tumours rely on the Warburg effect (aerobic glycolysis) to up-regulate glucose utilization, at the expense of the much more efficient mitochondrial oxidative phosphorylation (Ox Phos) pathway. However, emerging evidence is showing that not all tumours rely on aerobic glycolysis for their energy supplies. Some haematological cell types such as DLBCL exhibit gene signatures, suggesting that they are using both Ox Phos and glycolysis to fuel cell growth. We have already begun to explore this phenomenon in the contextof TRAIL-induced cell death in Mantle Cell Lymphoma (MCL). Our studies so far show that glucose restriction in Z138 cells (a MCL cell line) results in metabolic re-programming of the cells from aerobic glycolysis to Ox Phos. This switch desensitizes the cells to TRAIL-induced cell death and also to the Bcl-2 antagonist ABT-737, an intrinsic cell death stimulus. This metabolic switching results in marked changes in the morphology and mitochondrialproteome. On-goingexperiments areinvestigating the mechanisms of this phenomenon. Rather surprisingly, 2 deoxyglucose (2DG which, in contrast directly inhibits hexokinase and glycolysis, and enhances TRAIL killing. Thus, the effects of metabolic re-programming cannot be explained by mere inhibition of glucose-derived glycolytic flux.
Therefore, it is likely that other cell-signalling pathways such as AMPK and mTOR are involved. Currently there is intense interest in selectively targeting metabolic pathways for Cancer Therapy. This is an exciting field of research and we are uniquely placed to carry out this work as we have a Seahorse analyser to do cellular measurements of Ox Phos and glycolysis. We have already used thistechnology in two collaborative published studies (Bartesaghi et al, 2010; Capasso et al, 2010), and also in the Z138 studies described above. We have also developed sophisticated Proteomic methods for analysing the mitochondrial proteome in immuno-purified mitochondria isolated from patients with CLL. In addition, we have an internationally-recognised expertise in studying intrinsic and extrinsic cell death pathways, and the Unit also has in great strengths in genomic analysis/translational profiling. Combining all of these techniques provides a very powerful platform for studying the molecular mechanisms, underlying the interrelationships between cell death and metabolism in cancer.
Training Objectives:
This studentship will provide the individual with a wide range of skills of significant value. We expect the student to become proficient in molecular/cell biology, affinity purification, proteomics, translational profiling and subcellular localization technology. In addition the student will receive expert training in studying cellular metabolism. This is an exciting area of cell death and cancer cellbiology, and the student will gain a training which will yield not only novel results, but also a marketable expertise that will serve them well in their future career.
The laboratory has state-of-the-art facilities and is based at the MRC Toxicology Unit, which is located on the University of Leicester campus.
Application Details:
Candidates should possess, or expect to obtain, a good degree (1st or 2:1) in a relevant discipline. A background in biochemistry/cell biology and molecular biology is essential.
Applications to be made on the MRC studentship application form and should include a full CV. Queries on the application process or eligibility can be made to Amanda Harris at . Further details with regard to student eligibility requirements can be found at:
Closing date: Midday 31stJanuary 2011.
Interviews are expected to take place week commencing 7thFebruary 2011.