Andy Finch: Cell Metabolism and Homeostasis
Ribosome biogenesis is the process of generation of new ribosomes, involving four rRNAs, some 80 core ribosomal proteins (in eukaryotes) and over 200 transacting factors. It is a costly exercise for the cell in terms of energy and biosynthetic precursors and, as such, is tightly regulated at many stages. Unsurprisingly, many of the major oncogenes and tumour suppressor genes impinge on the regulation of ribosome biogenesis in several ways. Deregulation (both overactivation and impairment) of ribosome biogenesis leads to activation of tumour suppressive responses that a nascent tumour must circumvent in order to progress.
We are primarily interested in homeostatic models of regulation of ribosome biogenesis i.e. the activation of stress responses and consequent feedback mechanisms. Using this conceptual framework, we are trying to understand how deregulation of ribosome biogenesis leads to activation of tumour suppressive responses and what mechanisms cancer cells use to circumvent them. In addition, we are trying to see if we can interfere with ribosome biogenesis and elicit stress responses to try to therapeutically target cancer cells. Our research spans two main areas:
1. Metabolic changes due to action of oncogenes and tumour suppressors:
We use mass spectrometry to detect changes in cellular metabolites upon activation of oncogenes, alone & in combination with loss of tumour suppressor genes. We have a Q Exactive orbitrap mass spectrometer with an in-line Dionex RSLCnano UPLC that allows us to do elegant metabolomic experiments, including metabolic flux analyses. In these experiments a pulse of ‘labelled’ compound is applied to the cells and the metabolic fate of that compound can be traced by extraction and mass spectrometric detection. The potential applications of this technique are widespread and we are using using a variety of software approaches to maximise the power of these studies. The metabolic clues that these studies reveal are then followed up by molecular approaches in vitro and in vivo.
2. Specific ribosomal defects:
We are particularly interested in the late cytoplasmic stages of biogenesis (also called maturation) of the large (60S) ribosomal subunit. Two reactions (catalysed by the GTPases EFL1 and LSG1) are required to remove anti-association factors from the intersubunit interface. When these reactions are impaired, new ribosomal subunits cannot join to form a mature ribosome – a joining defect. We are studying stress responses that the cell mounts to these defects with a view to understanding the basic biology, translational implications (e.g. for syndromes with ribosome biogenesis defects) and possible cancer therapeutic targeting of these reactions.
IGMM Mass Spectrometry
We collaborate with many researchers throughout the institute and beyond on various mass spectrometry projects involving metabolomics and lipidomics.