Abstract 5017: Visualization of the mechanisms of metastasis within a biomimetic engineered tumor microenvironment encompassing a perfusable cylindrical 3D microvessel

Abstract

Abstract Metastasis is responsible for the majority of cancer related deaths; however, many of the biological and physical details surrounding the critical steps (e.g. invasion and intravasation) are largely unknown, in part due to the difficulty in recapitulating and visualizing these dynamic processes. To elucidate these mechanisms, we have developed an in vitro model of invasion and intravasation that comprises tumor cells embedded within an extracellular matrix (ECM) surrounding an engineered microvessel. The microvessel is cylindrical, 150 µm in diameter, and lined with endothelial cells forming a functional barrier that is maintained under constant perfusion at a shear stress of 2-8 dyne cm-2. Using this biomimetic tumor-microvessel platform, we have previously visualized invasion and intravasation of single MDA-MB-231 breast cancer cells into the microvessel and escape into flow. Here, we present mechanistic details of intravasation from both single tumor cells (MDA-MB-231) and mouse mammary tumor organoids (MMTV-PyMT). For single cells, we observe a mitosis-mediated mechanism of intravasation where tumor cell entry into flow is prefaced by cell division at the ECM-vessel interface. For tumor organoids, we see vascular deformation and destabilization from growing tumors that impinge upon proximal vessels, and that bulk intravasation is mediated by shear stress and tumor cell adhesion. As we characterize the various ways in which tumor cells interact with the vessel endothelium and intravasate, we can explore strategies involving the tumor vasculature and clinically relevant drugs to inhibit critical steps in the metastatic cascade. Citation Format: Andrew D. Wong, Vanesa Silvestri, Anderw J. Ewald, Peter C. Searson. Visualization of the mechanisms of metastasis within a biomimetic engineered tumor microenvironment encompassing a perfusable cylindrical 3D microvessel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5017. doi:10.1158/1538-7445.AM2017-5017