Abstract
Despite post-operative radio-chemotherapy, glioblastoma systematically locally recurs. Tumors contacting the periventricular zone (PVZ) show earlier and more distant relapses than tumors not contacting the PVZ. Since glioblastoma stem-like cells (GSCs) have been proposed to play a major role in glioblastoma recurrence, we decided to test whether GSC migration properties could be different according to their anatomical location (PVZ+/PVZ–). For that purpose, we established paired cultures of GSCs from the cortical area (CT) and the PVZ of glioblastoma patient tumors. We demonstrated that PVZ GSCs possess higher migration and invasion capacities than CT GSCs. We highlighted specific transcriptomic profiles in PVZ versus CT populations and identified a down-regulation of the RhoGTPase, RND1 in PVZ GSCs compared to CT GSCs. Overexpression of RND1, dramatically inhibited PVZ GSC migration and conversely, downregulation of RND1 increased CT GSC migration. Additionally, transcriptomic analyses also revealed a down-regulation of RND1 in glioblastoma compared to normal brain. Using the glioblastoma TCGA database, low levels of RND1 were also shown to correlate with a decreased overall survival of patients. Finally, based on signaling pathways activated in patients with low levels of RND1, we identified an RND1low signature of six genes (MET, LAMC1, ITGA5, COL5A1, COL3A1, COL1A2) that is an independent prognostic factor in glioblastoma. These findings contribute to explain the shorter time to progression of patients with PVZ involvement and, point out genes that establish the RND1low signature as key targets genes to impede tumor relapse after treatment.
Highlights
Despite combined modality treatment, including surgery and radio-chemotherapy, the prognosis of patients with glioblastoma remains extremely poor [1]
By using an original model of glioblastoma stem-like cells (GSCs) isolated from cortical area (CT) and periventricular zone (PVZ), we demonstrated that PVZ GSCs migrated faster and invaded more than CT GSCs and, that their migration may be controlled by RND1
We demonstrated that low-expression of RND1 in glioblastoma patient samples was correlated with a worse prognosis for patients
Summary
Despite combined modality treatment, including surgery and radio-chemotherapy, the prognosis of patients with glioblastoma remains extremely poor [1]. The failure of initial therapies, which is mainly dependent on tumor heterogeneity, is crucial in glioblastoma [3, 4]. High-resolution genome-wide studies have revealed that multiple clones harbouring a variety of genetic alterations coexist within the same tumor [6]. Molecular heterogeneity exists even at cellular level between cells that carry similar genetic alterations and is induced by environmental factors [3, 4]. Expanding single glioblastoma cells into clonal populations demonstrated unique properties including proliferation, differentiation, and different sensitivities to chemotherapeutic drugs [3]. Among patients with proneural tumor, an increased tumor heterogeneity was correlated to a decreased survival [4]
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