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Cell. 2014 Apr 24;157(3):580-94. doi: 10.1016/j.cell.2014.02.030. Epub 2014 Apr 10.

Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells.

Author information

1
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: suva.mario@mgh.harvard.edu.
2
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
3
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
4
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
5
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
6
Divisions of Neuro-Oncology and Hematology/Oncology and Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
7
Bioinformatics Program, Boston University, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
8
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
9
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
10
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02140, USA.
11
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
12
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: bernstein.bradley@mgh.harvard.edu.

Abstract

Developmental fate decisions are dictated by master transcription factors (TFs) that interact with cis-regulatory elements to direct transcriptional programs. Certain malignant tumors may also depend on cellular hierarchies reminiscent of normal development but superimposed on underlying genetic aberrations. In glioblastoma (GBM), a subset of stem-like tumor-propagating cells (TPCs) appears to drive tumor progression and underlie therapeutic resistance yet remain poorly understood. Here, we identify a core set of neurodevelopmental TFs (POU3F2, SOX2, SALL2, and OLIG2) essential for GBM propagation. These TFs coordinately bind and activate TPC-specific regulatory elements and are sufficient to fully reprogram differentiated GBM cells to "induced" TPCs, recapitulating the epigenetic landscape and phenotype of native TPCs. We reconstruct a network model that highlights critical interactions and identifies candidate therapeutic targets for eliminating TPCs. Our study establishes the epigenetic basis of a developmental hierarchy in GBM, provides detailed insight into underlying gene regulatory programs, and suggests attendant therapeutic strategies. PAPERCLIP.

PMID:
24726434
PMCID:
PMC4004670
DOI:
10.1016/j.cell.2014.02.030
[Indexed for MEDLINE]
Free PMC Article

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