DESCRIPTION (provided by applicant): Understanding of the fundamental mechanisms leading to metastatic cancer has been hampered by the need for models that replicate the in vivo situation, yet are amenable to tight control and facilitate high-resolution, time-lapse imagin and quantitative analysis of cell behavior. Over the past several years, we have developed microfluidic systems that are capable of simulating many steps of metastasis including tumor cell invasion, intravasation, trapping in the microcirculation or adhesion to the vessel walls, and extravasation into surrounding extracellular matrix. This prior work has shed new light on the interactions between a transmigrating tumor cell and the endothelium, the role of specific adhesion molecules, and the deformations of the cell and especially the cell nucleus, experience during the transmigration process. The object of this proposed study is to employ these recently developed assays in combination with new measurement methods to interrogate the changes in cell mechanics during the process of extravasation, and understand the nature of the cell-cell and cell-matrix force interactions. We also aim to investigate the nuclear deformations, changes in chromatin structure and the resulting changes in the transcriptome, which could have important implications for the subsequent ability of extravasated cells to form a new tumor. In close coordination with these experiments, computational models will be developed to simulate tumor cell / endothelial cell interactions, nuclear deformation, and the resulting changes in gene expression. We anticipate that these studies will provide new insights, and potentially enhance our ability to identify and screen for new therapies to inhibit the tendency for metastatic spread of disease.

PUBLIC HEALTH RELEVANCE Metastatic cancer is associated with more than 90% of all deaths due to cancer. Yet, there are no drugs available today that specifically target any of the major steps in the metastatic cascade. In this project, we seek to understand extravasation, the process by which tumor cells adhere to the walls of a blood vessel and escape into the surrounding tissues. We propose fundamental studies into the mechanisms of tumor cell extravasation, the forces and adhesions that enable it and effects this has on the gene expression profile of the extravasated cell. These studies will suggest new therapeutic targets to inhibit extravasation and provide new microfluidic assays that can be used in drug screening.