Abstract 1700: Novel microfluidic blood-brain niche to study breast cancer metastasis to the brain

Abstract

Abstract Metastasis from the primary tumor site to the brain is the most lethal complication of advanced cancer. Once a patient has developed brain metastasis, treatment involves surgical resection or radiation and is often only palliative. Poor prognosis following these therapies as well as the presence of concurrent disease outside of the nervous system emphasize the need for new systemic therapies that can reach and are active within the brain. In order to study the process of brain metastasis and develop potential therapies, models that mimic the human blood-brain niche must be used. Models currently utilized are murine in vivo models and various in vitro methods that do not accommodate all the biophysical characteristics of a blood-brain barrier. In vivo murine models are costly, time intensive, very slow to manifest metastases, and the metastatic process is seldom amenable to monitoring in real time. Current in vitro models are faster and more cost effective; however the models currently used do not have the same micro-environment complexity as “live” models. Here we describe a novel microfluidic device that accurately mimics the physical and cellular components of the human blood-brain niche to study the brain metastatic process. This device is composed of two chambers separated by a porous membrane. The top chamber and apical side of the membrane is seeded with human brain endothelial cells with and uses flow to mimic shear stress encountered within the vasculature. Cancer cells are introduced into this chamber in which they adhere to and migrate through the endothelium into the bottom chamber. The bottom chamber contains astrocytes suspended in a collagen gel to mimic the brain stroma and provide room for invading cancer cells to colonize and grow. Barrier integrity is monitored using TEER (trans-endothelial electrical resistance), and fluctuates as the tight junctions of the endothelium are compromised by invading cancer cells. Throughout all time points, from introduction into the flow chamber, adherence to the endothelium, extravasation through the barrier, migration into the stroma, and proliferation the cancer cells can be monitored via microscopy or TEER. This device provides a powerful novel tool to study the brain metastatic process and can be used to determine differences in brain metastatic potential of various cell lines or patient derived material, study the molecular mechanisms that promote brain metastasis, and test potential new therapies. Citation Format: Megan Altemus, Brendan Leung, Aki Morikawa, Michele Dziubinski, Maria Castro, Sofia Merajver. Novel microfluidic blood-brain niche to study breast cancer metastasis to the brain. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1700.