Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells.
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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: |
Year of Publication | 2014
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Journal | Cell
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Volume | 157
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Issue | 3
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Pages | 580-94
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Date Published | 2014 Apr 24
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ISSN | 1097-4172
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URL | |
DOI | 10.1016/j.cell.2014.02.030
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PubMed ID | 24726434
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PubMed Central ID | PMC4004670
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Grant list | U54 HG006991 / HG / NHGRI NIH HHS / United States
R01 NS032677 / NS / NINDS NIH HHS / United States
K12 CA090354 / CA / NCI NIH HHS / United States
Howard Hughes Medical Institute / United States
P50 CA165962 / CA / NCI NIH HHS / United States
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