Reconstructing and Reprogramming the Tumor-Propagating Potential of Glioblastoma Stem-like Cells
Gillespie, Shawn M.
Shalek, Alex K.
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CitationSuvà, Mario L., Esther Rheinbay, Shawn M. Gillespie, Anoop P. Patel, Hiroaki Wakimoto, Samuel D. Rabkin, Nicolo Riggi, et al. 2014. “Reconstructing and Reprogramming the Tumor-Propagating Potential of Glioblastoma Stem-Like Cells.” Cell 157 (3) (April): 580–594. doi:10.1016/j.cell.2014.02.030.
AbstractDevelopmental 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, 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 novel 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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:36880597
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