Journal
CELL
Volume 157, Issue 3, Pages 580-594Publisher
CELL PRESS
DOI: 10.1016/j.cell.2014.02.030
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Funding
- Oncosuisse [BIL-KFS02590- 02-2010]
- National Brain Tumor Society [NS032677]
- HHMI
- Howard Hughes Medical Institute
- Starr Cancer Consortium
- Harvard Stem Cell Institute
- Klarman Family Foundation
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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 tumorpropagating 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.
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