Cancer Res. 2020 May 4;canres.0855.2019. doi: 10.1158/0008-5472.CAN-19-0855. Online ahead of print.
Fabien Almairac1, Laurent Turchi2, Nathalie Sakakini3, David N Debruyne4, Sarah Elkeurti3, Elisabet Gjernes2, Beatrice Polo3, Laurence Bianchini5, Denys Fontaine6, Philippe Paquis6, Herve Chneiweiss7, Marie-Pierre Junier8, Patrick Verrando9, Fanny Burel-Vandenbos10, Thierry Virolle11
1 Neurosurgery, CHU de Nice / institut de biologie valrose.
2 Université Côte D’Azur, CNRS, Inserm, Institut de Biologie Valrose, Nice, DRCI, CHU de Nice.
3 institut de Biologie Valorise, INSERM/CNRS/UNSA.
4 Pediatric Oncology, Dana-Farber Cancer Institute.
5 Laboratory of solid tumor genetics, Université Côte d’Azur (UCA), CNRS UMR7284, INSERM U1081,Institute for Research on Cancer and Aging, Nice (IRCAN).
6 institut de Biologie Valorise/neurosurgery department, INSERM/CNRS/UNSA/CHU.
7 Glial Plasticity Lab, CNRS/Inserm/Sorbonne University.
8 IBPS-Neuroscience Paris Seine, Inserm U1130, CNRS UMR 8246, Université P. & M. Curie.
9 institut de Biologie Valrose, INSERM/CNRS/UNSA.
10 Pathology, Hôpital Pasteur.
11 institut de Biologie Valorise, INSERM/CNRS/UCA email@example.com.
There is great interest in understanding how the cancer stem cell population may be maintained in solid tumors. Here we show that tumor cells exhibiting stem-like properties and expression of pluripotency markers NANOG and OCT4 can arise from original differentiated tumor cells freshly isolated from human glioblastomas and which have never known any serum culture conditions. Induction of EGR1 by EGFR/ERK signaling promoted cell conversion from a less aggressive, more differentiated cellular state to a self-renewing and strongly tumorigenic state, expressing NANOG and OCT4. Expression of these pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating their capacity to change and dedifferentiate without any cell divisions. In differentiated GBM cells, ERK-mediated repression of miR-199a-3p induced EGR1 protein expression and triggered dedifferentiation. Overall, this signaling pathway constitutes an ERK-mediated “toggle switch” that promotes pluripotency marker expression and stem-like features in GBM cells.