Driving Neuronal Differentiation through Reversal of an ERK1/2-miR-124-SOX9 Axis Abrogates Glioblastoma Aggressiveness

• Published in: Cell reports (Cambridge) Vol. 28; no. 8; pp. 2064 - 2079.e11
• Main Authors: Sabelström, Hanna, Petri, Rebecca, Shchors, Ksenya, Jandial, Rahul, Schmidt, Christin, Sacheva, Rohit, Masic, Selma, Yuan, Edith, Fenster, Trenten, Martinez, Michael, Saxena, Supna, Nicolaides, Theodore P., Ilkhanizadeh, Shirin, Berger, Mitchel S., Snyder, Evan Y., Weiss, William A., Jakobsson, Johan, Persson, Anders I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.08.2019; Elsevier
• Subjects: Basic Medicine; brain; cancer; Cell and Molecular Biology; Cell- och molekylärbiologi; differentiation; glioblastoma; glioma; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; microRNA; neural stem cell; neurogenesis; neuron; tumor; neural stem cell; differentiation; glioblastoma; tumor; neurogenesis; neuron; glioma; microRNA; cancer; brain
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.07.071

Identifying cellular programs that drive cancers to be stem-like and treatment resistant is critical to improving outcomes in patients. Here, we demonstrate that constitutive extracellular signal-regulated kinase 1/2 (ERK1/2) activation sustains a stem-like state in glioblastoma (GBM), the most common primary malignant brain tumor. Pharmacological inhibition of ERK1/2 activation restores neurogenesis during murine astrocytoma formation, inducing neuronal differentiation in tumorspheres. Constitutive ERK1/2 activation globally regulates miRNA expression in murine and human GBMs, while neuronal differentiation of GBM tumorspheres following the inhibition of ERK1/2 activation requires the functional expression of miR-124 and the depletion of its target gene SOX9. Overexpression of miR124 depletes SOX9 in vivo and promotes a stem-like-to-neuronal transition, with reduced tumorigenicity and increased radiation sensitivity. Providing a rationale for reports demonstrating miR-124-induced abrogation of GBM aggressiveness, we conclude that reversal of an ERK1/2-miR-124-SOX9 axis induces a neuronal phenotype and that enforcing neuronal differentiation represents a therapeutic strategy to improve outcomes in GBM. [Display omitted] •Stem cell-derived glioma formation is accompanied by loss of neurogenesis•miR-124-dependent neuronal differentiation reduces glioblastoma (GBM) aggressiveness•An ERK1/2-miR-124-SOX9 axis regulates neuronal differentiation in GBM cells•An miR-124-induced neuronal phenotype sensitizes GBM cells to radiation Sabelström et al. show that the loss of neurogenesis is reversible during neural stem cell-derived glioma formation. Pharmacological inhibition of ERK1/2 globally regulates miRNAs and induces neuronal differentiation, a process that is dependent on the modulation of an miR-124-SOX9 axis in glioblastoma (GBM) cells. The overexpression of miR-124 induces neuronal differentiation that abrogates GBM aggressiveness.