Project 466583

Ovarian cancer is the most lethal gynecological cancer worldwide and has a 5-year survival rate of less than 40%. Women are usually diagnosed after their cancer has grown large and/or spread throughout the body. Many of these cancers will develop resistance to chemotherapy and stop responding to treatment, emphasizing the need for improved treatments. Recent studies have shown that components of the environment surrounding cancer cells, namely immune cells and structural proteins, play a key role in determining how quickly a cancer will grow, metastasize and whether or not it will respond to chemotherapy. Macrophages, a type of immune cell, are the most common immune cells found around ovarian cancer cells. When present in tumours, these cells help cancer cells evade immune detection and promote changes in structural proteins that can make cancer cells more drug resistant and motile. We plan to study how ovarian cancer cells change macrophage function and how this change impacts the structural matrix surrounding ovarian cancer. To study this, we will be focusing on how tissue transglutaminase (TG2) is involved in this process. TG2 is a protein with several functions; it is expressed in macrophages and is involved in structural protein remodeling. Furthermore, this protein promotes cancer cell migration and is associated with poor patient survival. We propose that loss of TG2 activity will prevent the remodeling process by inhibiting the macrophages. We will also examine whether new TG2 inhibitors can increase the ability of macrophages to target cancer cells and prevent tissue remodeling, leading to reduced cancer spread and increased survival in mice.