ERK-mediated Loss of miR-199a-3p and Induction of EGR1 Act as a “Toggle Switch” of GBM Cell Dedifferentiation Into NANOG- And OCT4-positive Cells

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

Affiliations

¹Neurosurgery, CHU de Nice / institut de biologie valrose.²Université Côte D’Azur, CNRS, Inserm, Institut de Biologie Valrose, Nice, DRCI, CHU de Nice.³institut de Biologie Valorise, INSERM/CNRS/UNSA.⁴Pediatric Oncology, Dana-Farber Cancer Institute.⁵Laboratory of solid tumor genetics, Université Côte d’Azur (UCA), CNRS UMR7284, INSERM U1081,Institute for Research on Cancer and Aging, Nice (IRCAN).⁶institut de Biologie Valorise/neurosurgery department, INSERM/CNRS/UNSA/CHU.⁷Glial Plasticity Lab, CNRS/Inserm/Sorbonne University.⁸IBPS-Neuroscience Paris Seine, Inserm U1130, CNRS UMR 8246, Université P. & M. Curie.⁹institut de Biologie Valrose, INSERM/CNRS/UNSA.¹⁰Pathology, Hôpital Pasteur.¹¹institut de Biologie Valorise, INSERM/CNRS/UCA thierry.virolle@icloud.com.

Abstract

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.

PMID: 32366479
DOI: 10.1158/0008-5472.CAN-19-0855