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

获得足够的营养来维持它们不受控制的生长是癌细胞存活和增殖的必要条件。实现这一目标的一个关键途径是通过一种称为巨胞饮作用的独特内吞过程清除和消化细胞外蛋白质（Commisso et al. 2013）。虽然大多数细胞通常不进行巨噬细胞作用，但它通过激活K-Ras突变而高度上调。25%的癌症，包括90%的胰腺癌，都有这种情况。阻断巨量红细胞增多症直接降低体内肿瘤生长，表明治疗潜力，但巨量红细胞增多体是如何形成的，以及它对其他细胞行为的影响尚不清楚（Buckley和King 2017）。这个为期4年的博士项目将研究致癌Ras突变如何导致细胞吞噬细胞外蛋白质，以及这如何影响同时被内化的细胞表面蛋白质的周转。这将通过诱导激活的K-Ras细胞来实现，允许我们随意打开和关闭Ras （Matthews et al. 2020）。这提供了一个独特的机会，了解这是如何导致细胞外蛋白质摄取，使用尖端的显微镜，分子生物学和蛋白质组学等技术。因此，该项目将在细胞生物学方面提供强大而广泛的培训，以确定癌细胞喂养所需的细胞骨架调节和内吞运输的基本机制。这是谢菲尔德大学的King和Matthews小组之间的合作项目。这提供了一个友好、包容、合作和资金充足的环境，可以在更广泛的mrc资助的博士联盟中使用尖端设施来开展这项工作。

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.