Identification of Mechanisms underlying deregulation of Cell Death Protein Signalling Complexes

Project Background:

Chemoresistance is a major obstacle in cancer chemotherapy – while some tumours develop chemoresistance during patient therapy some tumours are inherently chemoresistant. One such example is mesothelioma – a tumour usually associated with occupational exposure to the toxic agent asbestos. The inherent chemoresistance of many tumours suggests that several cell death signalling pathways are highly deregulated in this disease and are associated with disease progression. However, emerging evidence in a number of tumour types now suggests that ‘profiling’ of tumour cells in parallel with analysis of the molecular basis underlying the inherent resistance to cell death can be used to predict their response to subsequent therapy. Such information can then be used to identify agents that are selectively toxic to tumour cells but not to normal cells, thereby reducing the risk of adverse effects. We aim to apply this new knowledge to the study of chemoresistant tumours – for example, to date only limited information is available on the proteomic composition/status of key cell death protein signalling platforms in mesothelioma as compared to normal mesothelial cells.

This is an exciting field of research and we are uniquely placed to carry out this work. We have a Seahorse analyser to do live measurements of cellular bioenergetics and have already used this to great effect, in dissecting the mechanisms underlying metabolic regulation of apoptosis sensitivity in lymphoma cells (Robinson et al, 2012, Oncogene). We have also developed sophisticated Proteomic methods for analysing the mitochondrial proteome in immuno-purified mitochondria isolated from patient tumours and this method is easily adaptable to other chemoresistant tumours. In addition, we have an internationally recognised expertise in studying extrinsic and intrinsic cell death pathways including the Death-Inducing Signalling Complex (DISC)(Hughes, 2009, Mol Cell) and the recently identified ‘Ripoptosome’ (see Feoktistova et al; Tenev et al, 2011, Mol Cell). The MRC Toxicology Unit also has a considerable interest in genomic analysis/translational profiling of chemoresistant tumours (e.g. mesothelioma) and the above approach would directly complement this work. Combining all of these techniques provides a very powerful platform for studying the molecular mechanisms underlying the deregulation of cell death signalling complexes associated with chemoresistance in cancer cells.

Training Objectives:

The proposed studentship would provide the individual with a wide range of skills of significant value. We would expect the student to become proficient in molecular/cell biology, affinity purification, and proteomics. In addition the student will receive expert training in cell death signalling. This is an exciting area of cell death/cancer cell biology, and the student will gain training within an MRC-funded Unit, which will yield not only novel results, but also a marketable expertise that will serve them well in their future career