Advisor:

Dr. Susan Thomas (Georgia Institute of Technology)

Committee Members:

Dr. Andrés García (Georgia Institute of Technology)

Dr. Todd Sulchek (Georgia Institute of Technology)

Dr. John McDonald (Georgia Institute of Technology)

Dr. Gregory Lesinski (Emory University)

Engineered microfluidic platforms to enable the interrogation of metastatic extravasation under physiologically relevant hydrodynamic forces

Over 90% of all cancer-related deaths result from metastasis, a multistep process that occurs in either the lymphatics or in the blood vasculature. During metastasis, cancer cells leave the primary tumor, intravasate into the circulatory or lymphatic system, circulate until they are able to extravasate, and eventually take up residence in a secondary location of the body to form a metastatic tumor. In order to travel to distant sites in the body during the process of metastatic cancer extravasation, circulating tumor cells utilize a highly orchestrated adhesion cascade that begins with rolling adhesion to endothelial cells under a high shear environment. This process is driven by interactions between endothelial-presented selectins and glycan epitopes on selectin ligands present on the circulating cell’s surface. Selectin-selectin ligand interactions between circulating cancer cells and endothelial cells have been implicated in cancer metastasis, however, an outstanding problem in the field is the lack of effective systems to study the role of wall shear stress and cellular molecular profiles in initiating and sustaining increased selectin-ligand interactions, and how this may lead to enhanced metastatic propensity of circulating tumor cells. As such, the overall objective of this proposal is to engineer microfluidic platforms to permit the analysis of selectin-mediated adhesion and interrogation of cellular characteristics underlying selectin-selectin ligand interactions between the endothelium and metastatic cell subpopulations that occur during cancer dissemination in a tumor microenvironment. My central hypothesis is that microfluidic systems can be engineered to mimic the hemodynamic forces of the circulatory system or hydrodynamic forces of the lymphatic system, which can be used to interrogate cellular characteristics associated with adhesion in flow or the effects of altered microenvironments on metastasis.