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Ionizing radiations sustain Glioblastoma cell dedifferentiation to a stem phenotype through Survivin

P. Dahan1, J. Martinez Gala1, C. Delmas1, S. Monferran2, L. Malric1, D. Zentkowski1, V. Lubrano3, C. Toulas1, E. Cohen-Jonathan Moyal1, A. Lemarié1. 1INSERM U1037 CRCT, Experimental Therapeutics, Toulouse, France. 2INSERM U1037 CRCT, Molecular & Cellular Oncology, Toulouse, France. 3INSERM U825, Neurosurgery, Toulouse, France.

Glioblastomas (GBM) are some highly lethal brain tumors despite a conventional treatment associating surgical resection and subsequent radio-chemotherapy. Amongst these heterogeneous tumors, a subpopulation of chemo- and radioresistant GBM stem-like cells appears to be involved in the systematic GBM recurrence. Moreover, recent studies showed that differentiated tumor cells may have the ability to dedifferentiate and acquire a stem-like phenotype, a phenomenon also called plasticity, in response to microenvironment stresses such as hypoxia. We hypothesized that GBM cells could be subjected to a similar dedifferentiation process after ionizing radiations (IR), then supporting the GBM rapid recurrence after radiotherapy.
We demonstrated that the exposure of differentiated GBM cells to a subtoxic IR dose potentiated the long-term reacquisition of stem-associated properties such as the ability to generate primary and secondary neurospheres, the expression of stemness markers and an increased tumorigenicity. We also identified during this process an up-regulation of the anti-apoptotic protein survivin and we showed that its down-regulation by YM-155, a selective survivin inhibitor used in anti-cancer clinical trials, led to the blockade of the IR-induced plasticity.
Altogether, these results demonstrated that irradiation could regulate GBM cell dedifferentiation via a survivin-dependent pathway. Targeting the mechanisms associated with IR-induced plasticity will likely contribute to develop some innovating pharmacological strategies for an improved radiosensitization of these aggressive brain cancers.

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