Defining the pre-metastatic niche for colorectal cancer dissemination

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Colorectal cancer is a major cause of mortality and commonly associated with peritoneal metastasis in the abdomen. However, the peritoneum that covers internal organs and inner abdominal wall is poorly understood especially in terms of its ability to act as a premetastatic niche. Importantly, it is not clear why some patients develop peritoneal metastasis while others do not. Mesothelial cells that line the peritoneum act as an essential barrier to the invasion of free metastatic cancer cells. Mounting evidence suggests that when mesothelial cells encounter cancer cells, they undergo a transition with loss of intercellular junctions and poor adhesion to the basement membrane resulting in a defective barrier function. This exciting project aims to investigate the structure and function of the peritoneum of patients with peritoneal metastasis using a systems biology approach. Control samples will also be analysed from patients undergoing routine non-cancer surgery. Spatial transcriptomics, proteomics and detailed imaging will determine the unique gene and protein expression profile of peritoneum seeded with metastatic cancer cells. To define which molecules and key signalling pathways are essential to cancer cell attachment and invasion, a 3D co-culture model system of peritoneal metastasis will be developed that replicates findings from patients. Proposed outputs from this innovative project will elucidate the underlying biological mechanisms associated with peritoneal metastasis and may help identify early biomarkers of disease and offer targets for novel treatment strategies. The supervisory team are experts in their field with complementary multidisciplinary skillsets encompassing cancer cell biology, peritoneal disease modelling, pathology and surgery. The training environment is exceptional with both clinical and academic research exposure with excellent technical support from state-of-the-art core facilities.