Abstract 28: Role of CSF in facilitating synaptic plasticity in breast-to-brain metastasis

Abstract

Abstract Breast cancer is the most common cancer in women worldwide, and 10-30% of all breast cancer patients eventually develop brain metastases. Breast-to-brain metastases (BBMs) in stage IV breast carcinoma are concurrent with poor prognosis, neurological degeneration, <10-month survival, and account for 10% of all breast cancer related deaths. Accumulating scientific evidence underlines the importance of the tumor microenvironment in the establishment and progression of metastatic cancers. Due to the inability of current therapies to cross the blood brain barrier it has become increasingly important to study the interaction of BBMs with the neuronal microenvironment, to develop novel therapeutic interventions. Although the role of the blood brain barrier (BBB) in breast to brain metastasis has been widely studied, the contribution of the cerebrospinal fluid as a microenvironmental niche has been largely unexplored. The cerebrospinal fluid (CSF) produced by the choroid plexus (CP) cells in the brain, bathes the brain and spine; and serves as an initial point of contact to the brain for circulating breast cancer cells that reach the central nervous system. We treated EMT Her2+ BBM cells with choroid plexus derived artificial CSF. Both mRNA and protein analysis showed enhanced expression of Reelin in treated BBMs, compared to controls. Reelin is an extracellular matrix protein that mediates maturation and synaptic communication (plasticity) in neurons. It has also been shown to be a negative regulator of invasive properties in tumor cells. mRNA expression analysis also showed that the increase in Reelin in the CSF-treated BBMs was correlated with a marked reduction in the expression of invasive EMT markers, and enhanced expression of genes involved in neuronal synaptic plasticity. Correspondingly, through immunofluorescence studies on surgically resected brain metastases from patients, we were able to show to for the first time, that Her2+ metastases in the brain parenchyma display enhanced expression of markers of neuronal synaptic plasticity (SNAP25, NLGN1/2, ENAH, Neurexin). We were also able to show that Her2+ BBMs express high levels of Reelin, its receptor ApoER2 (LRP8) and intracellular mediator Dab1. This suggests that metastatic breast cancer cells mimic their immediate microenvironment to establish themselves in the brain. Our data indicates that the CP/CSF microenvironment aids in establishing tumor synaptic plasticity by inducing Reelin expression, and altering EMT profiles in BBMs. The contribution of the choroid plexus/CSF in the establishment of brain metastases in breast cancer has not been singularly explored, and this study provides novel insights into understanding its role as a microenvironmental niche. Citation Format: Krutika Deshpande, Alex Julian, Behnaz Saatian, Josh Neman. Role of CSF in facilitating synaptic plasticity in breast-to-brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 28.