| Literature DB >> 24726434 |
Mario L Suvà1, Esther Rheinbay2, Shawn M Gillespie2, Anoop P Patel3, Hiroaki Wakimoto4, Samuel D Rabkin4, Nicolo Riggi5, Andrew S Chi6, Daniel P Cahill4, Brian V Nahed4, William T Curry4, Robert L Martuza4, Miguel N Rivera5, Nikki Rossetti5, Simon Kasif7, Samantha Beik8, Sabah Kadri8, Itay Tirosh8, Ivo Wortman8, Alex K Shalek9, Orit Rozenblatt-Rosen8, Aviv Regev10, David N Louis11, Bradley E Bernstein12.
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:Entities:
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Year: 2014 PMID： 24726434 PMCID： PMC4004670 DOI： 10.1016/j.cell.2014.02.030
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582