RND1 regulates migration of human glioblastoma stem-like cells according to their anatomical localization and defines a prognostic signature in glioblastoma
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Sabrina Boyrie1,2, Caroline Delmas1,2, Anthony Lemarié1,3, Vincent Lubrano4,5, Perrine Dahan1, Laure Malric1,3, José Luis6, Julia Gilhodes2, Marie Tosolini1, Laetitia Mouly1,3, Maxime Lehmann7, Christine Toulas1,2,*, Elizabeth Cohen-Jonathan Moyal1,2,3,* and Sylvie Monferran1,3,*
1INSERM UMR1037, Cancer Research Center of Toulouse, Oncopole, Toulouse, France
2Institut Claudius Regaud, IUCT-O, Toulouse, France
3Université Toulouse III, Toulouse, France
4INSERM UMR825, Université Toulouse III, Toulouse, France
5Service de Neurochirurgie, Centre Hospitalier de Purpan, Université Toulouse III, Toulouse, France
6Centre de Recherche en Oncologie biologique et Oncopharmacologie (CRO2), INSERM UMR 911, Aix-Marseille Université, Marseille, France
7UMR 7213 CNRS, Laboratoire de Biophotonique et Pharmacologie, Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, 67401 Illkirch, France
*These authors contributed equally to this work
Sylvie Monferran, email: firstname.lastname@example.org
Christine Toulas, email: email@example.com
Elizabeth Cohen-Jonathan Moyal, email: firstname.lastname@example.org
Keywords: glioblastoma stem-like cells; periventricular zone; migration; prognostic signature; RND1
Received: February 20, 2018 Accepted: July 31, 2018 Published: September 18, 2018
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.
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