Understanding how oncogene-induced drinking drives cancer cell biology and disease

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Obtaining enough nutrients to sustain their unregulated growth is essential for cancer cell survival and proliferation. A key way in which this is achieved is through scavenging and digesting extracellular proteins through a unique endocytic process called macropinocytosis (Commisso et al. 2013). Whilst most cells don't normally perform macropinocytosis, it is highly upregulated by activating mutations in K-Ras. These are found in 25% of all cancers, including 90% of pancreatic cancers. Blocking macropinocytosis directly reduces tumour growth in vivo, indicating therapeutic potential, but the how macropinosomes are formed and what affects this has on other cell behaviours remains unclear (Buckley and King 2017).This 4-year PhD project will investigate how oncogenic Ras mutations cause cells to engulf extracellular proteins and how this affects turnover of the cell surface proteins that get internalised at the same time. This will be achieved using inducibly activated K-Ras cells, allowing us to turn Ras on and off at will (Matthews et al. 2020). This provides a unique opportunity to understand how this leads to extracellular protein uptake, using techniques such as cutting-edge microscopy, molecular biology and proteomics. The project will therefore provide a strong and broad training in cell biology, to identify the fundamental mechanisms of cytoskeletal regulation and endocytic trafficking required for cancer cell feeding. This is a collaborative project between the King and Matthews groups at the University of Sheffield. This provides a friendly, inclusive, collaborative and well-funded environment with access to cutting edge facilities to undertake this work, within the broader MRC-funded PhD consortium.