Recapitulating Dynamic Disease States from In Vitro to In Vivo: The Pathophysiology of Cell Fusion in Breast Cancer Metastasis and New Model Systems of Intracranial Aneurysm

Abstract

Disease pathophysiology and potential therapies are studied using a variety of models. The specific models, or particular set of experiments, determine what questions can be answered about the disease model system. Here we look at three different model systems for studying both cell fusion in breast cancer metastasis and intracranial aneurysms. The bulk of this thesis work focuses on studying intracranial aneurysms. Intracranial Aneurysms (IAs) are weakened bulging points in blood vessels that upon rupture result in a devastating form of stroke known as a subarachnoid hemorrhage. Numerous features of IAs have been identified including the loss of elastin and collagen structure, increased immune infiltration, heightened cell activation and aberrant blood flow (hemodynamic forces). Although IAs have been studied for decades there are still no definitive causes for aneurysm stability vs growth and ultimately rupture. This is likely due to limited research focusing on creating links between the multiple driving forces of aneurysm progression. Unidentified hemodynamic forces are thought to be the main factor in the initiation of IA growth, yet there is almost no research that looks at both the aberrant flow patterns within IAs and the resulting biological response. While there are multiple methods of treatment, all come with high risk to the patient and are designed to mechanically occlude blood flow while ignoring the underlying biological mechanisms at play. Current model systems both in vivo and in vitro either lack physiological relevance or are limited in their ability to test therapeutic options through modified conventional means. Here, we have established an in vivo model of IA with increased physiologic relevance that can be utilized for the development of targeted therapeutic strategies and an in vitro model of IA that can be utilized to study the biological response of endothelial cells in response to specific blood flow patterns and the resulting hemodynamic forces.