Presenter: Benjamin Gordon
Mentor: Jan Kitajewski, PhD
Breast cancer is the second leading cause of cancer-related mortality in women. The primary tumor doesn’t normally cause death, but the spread of the disease does. Up to 20% of breast cancer diagnoses are triple negative breast cancer (TNBC), and the five-year survival rate for the disease in its late stages is as low as 11%.
TNBC is unresponsive to hormonal and targeted therapies of other types of breast cancer. Surgery and adjuvant chemotherapy are effective treatment options for the disease’s early stages, but there are very few therapeutic options for the spread of TNBC in its late stages. For metastasis to occur, circulating tumor cells (CTCs) must cross the endothelial barrier twice: first to migrate away from the primary tumor and enter systemic circulation (intravasation), and then to exit circulation to colonize other tissues (extravasation). Understanding the mechanisms of tumor-endothelial interactions during metastasis may provide avenues to develop novel therapeutic agents to help patients with metastatic breast cancer.
Gordon and his colleagues are currently exploring the role of Jagged-1 (Jag1), a Serrate class Notch ligand, in the metastatic process. Jag1 is expressed in many human TNBC cell lines and its expression is associated with a worse prognosis in the clinic. The laboratory’s preliminary data suggest that Jag1 presented on tumor cells promotes extravasation behavior, particularly TNBC binding to endothelium and subsequent transendothelial migration (TEM). A hypothesis has been developed where the tumor derived Jag1 is necessary to activate signaling in either tumor or endothelial cells to permit extravasation phenotypes and, by extension, metastasis. Studies conducted in the Kitajewski laboratory have blocked Jag1 function using two methods: Jag1-specific Notch decoys and Jag1 deletion via CRISPR/Ca9.