Abstract 3041: GPR56 promotes the adhesion of glioma stem-like cells to the perivascular niche and regulates cell fate

Abstract

Abstract INTRODUCTION Gliobastomas (GBM) are the most aggressive and frequent human malignancies in the central nervous system. A small population of cells within the bulk of these tumors displays properties of normal neural stem cells (NSC). Accordingly, these cells are referred to as glioma stem-like initiating cells (GIC). Thus, deregulation of mechanisms that control NSC biology might contribute to the pathogenesis of GBM. NSC and GIC are localized to the perivascular space where they reside in close apposition to blood vessels (BV), which promote self-renewal and keep these cells in an undifferentiated state. GPR56 is an adhesion G-protein coupled receptor expressed in neural progenitors in the embryonic and adult brain and plays an indispensable role in cortical development. Knockout mice studies show that GPR56 mediates the attachment of radial glial endfeet to pial basement membrane (BM). Some of the components of the pial BM are also present in the extracellular matrix surrounding BV, such as laminin and collagen. Therefore, we hypothesized that GPR56 might mediate NSC/GIC localization to the perivascular niche thus contributing to their stem-related properties. EXPERIMENTAL PROCEDURES Here, we have compared the expression of GPR56 in neural progenitors versus more differentiated progeny. In addition, we have assessed the role of GPR56 in the neural stem-like properties of GIC, including their differentiation into more mesenchymal cell types such as endothelial cells or pericytes, by gain- and loss-of-function studies. RESULTS We have found that GPR56 is highly expressed in NSC and its expression is downregulated during differentiation. We have also observed that GPR56 is expressed in cells that reside in the perivascular niche. GPR56-knockdown GIC display impaired adhesion to endothelial cells (EC), whereas GPR56 overexpression increases their adhesion to EC. Furthermore, loss of GPR56 increases the ability of GIC to express endothelial/pericyte markers when co-cultured with EC and increases the CD44+ population, suggesting that GPR56 inhibits the acquisition of a mesenchymal-like phenotype. CONCLUSIONS Taken together, our findings indicate that GPR56 mediates the adhesion of GIC to EC. Moreover, GPR56 inhibits the acquisition of mesenchymal features. Therefore, we suggest that GPR56 might mediate the attachment of GIC to the perivascular niche while preserving their neural stem-like properties by preventing the acquisition of a mesenchymal-like phenotype. Citation Format: Marta Moreno, Stefanie Giera, Xianhua Piao, Nuria de la Iglesia. GPR56 promotes the adhesion of glioma stem-like cells to the perivascular niche and regulates cell fate. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3041. doi:10.1158/1538-7445.AM2014-3041