Journal
CELL REPORTS
Volume 28, Issue 8, Pages 2064-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.07.071
Keywords
-
Categories
Funding
- UC CRCC
- American Brain Tumor Association (ABTA) Collaboration Grant - Humor to Fight the Tumor Foundation
- Children's Tumor Foundation
- National Brain Tumor Society
- Loglio Collaborative
- TDC Foundation
- Solomon R. Guggenheim Foundation endowment fund
- Swedish Research Council
- European Molecular Biology Organization
- Foundation Blanceflor Boncompagni Ludovisi, nee Bildt
- ABTA Basic Research Fellowship
- [R21NS088114]
- [R01NS091620]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available