Engineered microfluidic platforms to enable the interrogation of metastatic extravasation under physiologically relevant hydrodynamic forces
Birmingham, Katherine G.
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Over 90% of all cancer-related deaths result from metastasis, a multistep process that occurs in the blood or lymphatic vasculature under hydrodynamic forces. During metastasis, cancer cells leave the primary tumor, intravasate into the circulatory or lymphatic system, circulate until they can extravasate, and take up residence in a secondary location of the body to form a metastatic tumor. In order to leave the vasculature during 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 selectin ligands present on the circulating cell’s surface. These selectin-selectin ligand interactions 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 these interactions, and how this may lead to enhanced metastatic capacity of circulating tumor cells. As such, the overall objective of this thesis 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.