Project 458338

Gastric adenocarcinoma (GCa) is one of the leading causes of cancer death globally. One of the distinguishing features of GCa is its propensity to spread into the peritoneal layer of the abdominal cavity, causing intractable symptoms of pain and ascites that are difficult to control. Various patient and tumour characteristics are more common in those who develop peritoneal metastasis. This observation suggests that there may be distinct molecular mechanisms that lead to peritoneal metastasis, as well as specific mitigating strategies that could prevent peritoneal spread. Plk4 is a member of the polo family of serine/threonine protein kinases. Our laboratory has shown that Plk4 also promotes cancer cell migration, invasion and metastasis in breast cancer models. Plk4's effect on migration and invasion could be mediated through several pathways, most notably small Rho GTPases and their linked Guanine Exchange Factors (GEFs). My project seeks to functionally validate Plk4 as a target in the prevention of peritoneal dissemination of GCa and explore the underlying mechanisms. I hypothesize that Plk4 facilitates GCa peritoneal metastasis by by enhancing cell migration and invasion of the peritoneum through phosphorylating PREX2, a Rac1 GEF. Thus far, I have shown that Plk4 enhances GCa migration and invasion and that Plk4 and PREX2 interact physically and functionally. I have also developed a novel Ex Vivo human peritoneal explant model. I aim to use the model to show that Plk4, through PREX2, promotes the initial clearance of peritoneal mesothelial cells by GCa cells, increases motility of GCa cells within the peritoneum, and drives invasion. This model will also be used to discover novel mediators of peritoneal metastasis. By uncovering the specific pathways that mediate this pattern of spread, my project will reveal novel therapeutic targets, bringing us closer to the goal of improving quantity and quality of life in patients at high risk of peritoneal metastasis.