Grant: CIHR Fellowship

Breast cancer is the most common cancer in females worldwide. Metastasis is the occurrence of tumors at distant sites in the body and is a major predictor of cancer outcome. Neutrophils are the most abundant white blood cells in the blood and play a significant role in shaping the immune response. Paradoxically, neutrophil infiltration of tumors is correlated with poor prognosis and decreased survival in breast cancer and several malignancies. Recently, it was shown that neutrophils can release their cellular contents in a mesh of DNA (similar to a spider's web) in what has been described as neutrophil extracellular trap (NET) formation. Importantly, breast cancer cells have been shown to induce NET formation and NETs provide anchorage for circulating tumor cells and thereby serve as hot spots for metastasis. Additionally, several proteins released during NETs formation damage blood vessels and contribute to mortality in breast cancer patients. Hence, inhibiting NET formation is beneficial in breast cancer therapy. The role of immune signaling pathways in the formation of NETs is unknown. In particular, SYK is a protein that functions as an "on or off" switch in neutrophils but its role in NET formation is unknown. My goal is to decipher the role of SYK in NET formation. Our current models suggest that inhibition of SYK prevents NET formation which leads to decrease in growth and invasion of breast cancer cells. We will engineer a tumor microenvironment of metastasis involving endothelial cells, neutrophils and breast cancer cells and investigate the effect of SYK inhibition on NET formation and metastasis using laboratory and animal models. We will use nanoparticles to deliver SYK inhibitor to neutrophils as a strategy to inhibit NET formation and metastasis in breast cancer. These studies will create new knowledge on the role of SYK in NET formation and develop new therapy targeting SYK pathway for the prevention of metastasis in breast cancer patients.