Reconstructing and Reprogramming the Tumor-Propagating Potential of Glioblastoma Stem-like Cells
Author(s)
Suvà, Mario L.; Rheinbay, Esther; Gillespie, Shawn M.; Patel, Anoop P.; Wakimoto, Hiroaki; Rabkin, Samuel D.; Riggi, Nicolo; Chi, Andrew S.; Cahill, Daniel P.; Nahed, Brian V.; Curry, William T.; Martuza, Robert L.; Rivera, Miguel N.; Rossetti, Nikki; Kasif, Simon; Beik, Samantha; Kadri, Sabah; Tirosh, Itay; Wortman, Ivo; Shalek, Alex K.; Rozenblatt-Rosen, Orit; Regev, Aviv; Louis, David N.; Bernstein, Bradley E.; ... Show more Show less
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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 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.
Date issued
2014-04Department
Massachusetts Institute of Technology. Department of BiologyJournal
Cell
Publisher
Elsevier
Citation
Suv?, Mario?L. et al. “Reconstructing and Reprogramming the Tumor-Propagating Potential of Glioblastoma Stem-like Cells.” Cell 157.3 (2014): 580–594.
Version: Author's final manuscript
ISSN
0092-8674
1097-4172