ATPS-11DEXAMETHASONE INDUCES A MESENCHYMAL SHIFT IN GLIOBLASTOMA STEM CELLS

Abstract

Dexamethasone is routinely administered to manage cerebral edema in glioblastoma (GBM). Its impact on molecular mechanisms driving GBM invasion is unknown. Utilizing radiogenomic strategies, we previously introduced Periostin as key mediator of GBM associated edema and cellular invasion. We observed that multiple molecular targets of Dexamethasone are significantly upregulated and overlap with Periostin correlated genes, including CEBPB. We hypothesized that Dexamethasone, by regulating Periostin correlated genes, promotes a mesenchymal program of tumor cells including Glioblastoma Stem Cells (GSCs). A panel of GSCs were profiled for Periostin correlated genes after Dexamethasone treatment, using microarray, qPCR and Western blotting. Tests for self-renewal (limiting dilution assay), differentiation (neural lineage marker analysis), invasion (Boyden chamber) and proliferation (BrdU) were performed after Dexamethasone exposure. Three independent GSC lines were used to generate orthotopic tumors and mice were then treated with Dexamethasone (intraperitoneal). Differentially expressed genes in GSC derived tumors (total RNA from cells of human origin were isolated using human specific Anti- HLA Class I ABC antibody by FACS) upon Dexamethasone exposure were evaluated with connectivity map (cmap) to screen for specific therapeutics. Cells treated with Dexamethasone showed an increased CEBPB expression, indicating a more aggressive mesenchymal gene signature. Histopathologic validation of orthotopic tumors supported this effect of Dexamethasone. Treatment with specific, FDA approved therapeutics in combination with Dexamethasone suppressed Periostin correlated gene levels and subsequently reduced this mesenchymal shift. In this preclinical study we showed that Dexamethasone promotes a molecular mesenchymal shift by elevating CEBPB expression levels in both, in vitro and in vivo. These results warrant an evaluation of Dexamethasone for managing edema in glioblastoma patients. Neutralizing side effects of Dexamethasone by adding our shortlisted drugs may improve GBM patient care.