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DOCK4 promotes loss of proliferation in glioblastoma progenitor cells through nuclear beta-catenin accumulation and subsequent miR-302-367 cluster expression

Abstract

Glioblastomas (GBM) are lethal primitive brain tumours characterized by a strong intra-tumour heterogeneity. We observed in GBM tissues the coexistence of functionally divergent micro-territories either enriched in more differentiated and non-mitotic cells or in mitotic undifferentiated OLIG2 positive cells while sharing similar genomic abnormalities. Understanding the formation of such functionally divergent micro-territories in glioblastomas (GBM) is essential to comprehend GBM biogenesis, plasticity and to develop therapies. Here we report an unexpected anti-proliferative role of beta-catenin in non-mitotic differentiated GBM cells. By cell type specific stimulation of miR-302, which directly represses cyclin D1 and stemness features, beta-catenin is capable to change its known proliferative function. Nuclear beta-catenin accumulation in non-mitotic cells is due to a feed forward mechanism between DOCK4 and beta-catenin, allowed by increased GSK3-beta activity. DOCK4 over expression suppresses selfrenewal and tumorigenicity of GBM stem-like cells. Accordingly in the frame of GBM median of survival, increased level of DOCK4 predicts improved patient survival.

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Acknowledgements

This work was supported by grants from the Association pour la Recherche sur le Cancer (subvention 3161), Association Sauvons Laura, ADerTU, Association Dimitri Bessière, Agence Nationale pour la Recherche (ANR Jeunes Chercheurs, Jeunes Chercheuses, «GLIOMIRSTEM project»), Fondation de France, ARC projet (SFI20111203773), INCA PLBIO2012, ITMO CANCER plan cancer, INSERM, UNSA. We thank A Borderie, S Bestrée, C Hagnere, F Frassinetti, S Rekima, AC Peyron and F Keslair for their technical assistance and C. Colin for the statistical analysis. We thank Doctor Enzo Lalli for providing the PKF115-584 inhibitor and Doctor Andreas Schedl for the mYhBCATf and the TopFlash reporter plasmid. We thank Doctor Ellen Van Obberghen-Schilling for grammatical corrections.

Author contributions

DND, LT, FBV and TV designed the research. DND, FA, LT, FBV, VV, NBK performed the experiments. DND, NBK, DFB, FB, MF, FA, LT, FBV, PL and PV analyzed the data. DND, LT, DF, PP, FBV, MPJ, HC and TV discussed the data. DND and MPJ has corrected the manuscript. TV wrote the manuscript.

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Correspondence to T Virolle.

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Debruyne, D., Turchi, L., Burel-Vandenbos, F. et al. DOCK4 promotes loss of proliferation in glioblastoma progenitor cells through nuclear beta-catenin accumulation and subsequent miR-302-367 cluster expression. Oncogene 37, 241–254 (2018). https://doi.org/10.1038/onc.2017.323

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