Elucidating how coordination of mRNA-translation and membrane trafficking influences fibrosis and tumour niche formation in the liver

Cells have specialised machinery - called ribosomes - for making proteins. When cells are dividing, they put a lot of resources into manufacturing proteins to make more cells. Much research has focussed on how ribosomes make cellular proteins to support cell division to make new cells, and this has been important to understand diseases in which cell division is uncontrolled - such as cancer. However, cells don't divide much in healthy adults, so protein production tends to be devoted to tissue maintenance - in which old cells are replaced with new ones - and wound healing/tissue repair processes. Indeed, during wound healing cells start to make lots more proteins; not for cell growth but for secretion from the cells. Many of these secreted proteins make up the connective tissue, or extracellular matrix, that repair wounds, and we term this connective tissue - the 'extracellular matrix'. Moreover, extracellular matrix proteins need to be transported through a series of compartments in the cell to be secreted in the appropriate manner, and this complex transport process is termed intracellular protein 'trafficking'. In healthy individuals, extracellular matrix production is controlled and timed appropriately, so that it can be turned-off when the wound is repaired and/or an old cell is replaced with a new one. However, following certain toxic insults - such as paracetamol poisoning - cells in the liver become damaged in such a way as to make them 'senescent' - a damaged state which is akin to premature ageing. Damaged 'senescent' cells then start to make lots of extracellular matrix proteins which they release in an excessive and uncontrolled way leading to scar formation and, ultimately to liver fibrosis and cirrhosis. This is a key concern, because this cirrhotic scar tissue forms a breeding ground for other diseases, such as liver cancer.

We propose that damaged/senescent liver cells must re-structure their ribosomes and their intracellular protein trafficking machinery to enable the production and release of all these extracellular matrix proteins. This research programme will combine state-of-the-art methodologies, such as advanced 3-dimensional microscopy, to investigate the mechanisms linking increased ribosome function with alterations to protein trafficking machinery as liver cells become senescent. Specifically, we will elucidate the cellular mechanisms that link the production of the various extracellular matrix proteins by ribosomes with the trafficking machinery that takes them to the cell surface. Then we will investigate how these processes may be coordinated as cells attempt to maintain homeostasis in the face of increased demand to secrete proteins in senescent cells. Integral to this research programme will be the use of laboratory mouse models in which senescence has been induced in the liver, by dietary, toxic and targeted changes to the DNA. We will then pursue these studies to find out how these alterations to the protein synthesis and secretory machinery that occur during liver senescence contribute to the initiation of liver cancer.

The combination of these approaches will enable us to assemble a detailed understanding of the relationship between secretory protein production, protein trafficking and build-up of extracellular matrix proteins outside cells during liver fibrosis/scarring and the initiation of liver cancer. We anticipate that this detailed mechanistic understanding will facilitate identification of individuals particularly at risk of fibrotic liver disease and cancer and assist with preventative interventions.