Investigating the Role of the Extracellular Matrix in Metastasis and Chemo-Resistance

Metastasis, the dissemination of cells from the primary tumor, is the leading cause of death in cancer patients. For metastatic breast cancer, chemotherapy remains the standard of care. While the benefits of chemotherapy for the treatment of metastatic disease have been well documented, over 50% of triple-negative breast cancer patients become resistant to chemotherapy. Increasing our understanding of the mechanisms driving metastasis and drug resistance will help identify biomarkers that can be used to predict them, and characterize targetable signaling pathways to that can be used to prevent them. It is now well appreciated that the tumor microenvironment can contribute to tumor progression and metastasis. The extracellular matrix (ECM), forms a complex scaffold of proteins that provides both structure and signals to the tumor cells. However, its role in driving invasion and metastasis and how it could affect response to chemotherapy remains unexplored. The main goal of this proposal is to investigate the role of the ECM in metastasis and chemo-resistance, using an interdisciplinary approach that will combine cell biology, intravital imaging, systems biology and implantable devices. First, we have shown that gradients of fibronectin can promote directional motility of tumor cells, a process important for metastasis. When highly metastatic tumor cells are subject to gradients of EGF and fibronectin simultaneously, they will invade even more than with each cue alone.

The goal of Aim 1 is to investigate the contribution of ECM versus growth factor cues during local invasion and metastatic colonization. Second, preliminary investigation into the effect of chemotherapeutic drugs on highly invasive tumor cells revealed that they can have differential effects on cell proliferation and migration, and can also regulate ECM sensitivity and organization. Aim 2 will identify ECM combinations that affect cell growth and migration in response to clinically relevant chemotherapy regimens and perform a CRISPR knockout screen of ECM-regulator proteins to identify novel genes regulating chemo-sensitivity. I also propose an extensive training program that will support my transition to independence.