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

Sabelström, H. LU ; Petri, Rebecca LU ; Shchors, Ksenya; Jandial, R.; Schmidt, Christin; Sacheva, Rohit; Masic, S.; Yuan, E.; Fenster, Trenten and Martinez, Michael, et al. (2019) In Cell Reports 28(8). p.11-2079
Abstract

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... (More)

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. 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.

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published
subject
keywords
brain, cancer, differentiation, glioblastoma, glioma, microRNA, neural stem cell, neurogenesis, neuron, tumor
in
Cell Reports
volume
28
issue
8
pages
11 - 2079
publisher
Cell Press
external identifiers
  • scopus:85070223475
ISSN
2211-1247
DOI
10.1016/j.celrep.2019.07.071
language
English
LU publication?
yes
id
9d11bdaf-9e83-465e-9151-92bdfc21ae2a
date added to LUP
2019-08-27 11:31:19
date last changed
2019-09-11 04:22:45
@article{9d11bdaf-9e83-465e-9151-92bdfc21ae2a,
  abstract     = {<p>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. 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.</p>},
  author       = {Sabelström, H. and Petri, Rebecca and Shchors, Ksenya and Jandial, R. and Schmidt, Christin and Sacheva, Rohit and Masic, S. and Yuan, E. and Fenster, Trenten and Martinez, Michael and Saxena, S. and Nicolaides, Theodore P. and Ilkhanizadeh, Shirin and Berger, Mitchel S. and Snyder, Evan Y. and Weiss, William A. and Jakobsson, J. and Persson, Anders I.},
  issn         = {2211-1247},
  keyword      = {brain,cancer,differentiation,glioblastoma,glioma,microRNA,neural stem cell,neurogenesis,neuron,tumor},
  language     = {eng},
  number       = {8},
  pages        = {11--2079},
  publisher    = {Cell Press},
  series       = {Cell Reports},
  title        = {Driving Neuronal Differentiation through Reversal of an ERK1/2-miR-124-SOX9 Axis Abrogates Glioblastoma Aggressiveness},
  url          = {http://dx.doi.org/10.1016/j.celrep.2019.07.071},
  volume       = {28},
  year         = {2019},
}