Project 467257

Rhabdomyosarcoma (RMS) is the most common soft-tissue cancer in children and has a particularly poor prognosis with a 5 year survival rate of 30% in individuals with metastatic (spreading throughout the body) RMS. What leads to this state is muscle cells (myocytes) uncontrollably dividing, resulting in tumours which can invade and destroy healthy tissue. Our laboratory has identified the protein pannexin1 (PANX1) to be a novel regulator of muscle growth (myogenesis). PANX1 is a transport channel that lies on the surface of many cell types, including myocytes allowing for the passage of molecules across the cell membrane. Levels of PANX1 are low in immature myocytes and increase as the cells develop. Blocking PANX1 has been shown to prevent muscle cells from fully developing while increasing the expression of PANX1 has promoted development. Specifically in RMS, PANX1 levels are seen to be low. Our lab has shown that increasing the number of these channels has reduced tumour sizes both in 3D and animal models. The process through which this happens is independent of PANX1 acting as a channel for other molecules. The lab has thus outlined the whole set of molecular interactions (interactome) that PANX1 takes part in including a variety of proteins. This proposed research project aims to uncover the exact mechanism by which PANX1 expression inhibits RMS. Specifically, using high-throughput screening and automated microscopy, we hope to develop a functional method to measure cell proliferation and viability. Additionally, we want to use the functional screen to target the PANX1 interactome using RMS cell lines. This will help identify the PANX1 interactions that regulate RMS development and potentially lead to new targets for therapy.