Investigation of the contribution of redox stress to the therapy resistance of cells experiencing cycling oxygen levels

Hypoxia is a major barrier to successful cancer treatment as the more hypoxic a tumour, the less well patients respond. This project will focus on the physiologically relevant condition of cyclic hypoxia in which cancer cells experience fluctuations in oxygen levels as opposed to constant exposure to hypoxia. Recent findings from the Hammond lab suggest that the cellular response to cyclic hypoxia differs significantly from constant exposure and that this includes the contribution of changes in REDOX in the cyclic conditions. Understanding the dynamics of REDOX elements in biological systems is of major importance because of its roles in basic biology, agriculture, disease and medicine. However, quantifying changes in REDOX elements remains a major challenge for chemical biology. Key elements involved in defining the cellular REDOX environment include reactive oxygen species (ROS), reactive nitrogen species (RNS), sulfur-containing molecules including H2S and glutathione (GSH), hypoxia (lower than normal [O2]), and post-translational modification of amino acid residues in proteins. The relative concentration and interaction of these components defines the cellular REDOX environment, which is intrinsically linked to metabolism through processes such as glycolysis and oxidative phosphorylation. Cellular metabolism and REDOX state are in turn linked to epigenetic regulation, because modifications to chromatin involve consumption of important metabolites and REDOX-active molecules. Consequently, both metabolism and the REDOX environment can affect transcription through chromatin remodelling, and therefore cell fate decisions are closely linked to changes in metabolic activity and the REDOX environment. This project will investigate REDOX stress in cyclic hypoxia and how this contributes to biological response and sensitivity to cancer therapies. Specific approaches will include, for example, gene expression analysis (RNA-seq) of cells in both constant and cyclic hypoxia. This project will also benefit from early access to probes being generated in the Conway lab which will allow characterisation of REDOX stress.