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Cell DOI:10.1016/j.cell.2014.02.030

Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells.

Publication TypeJournal Article
Year of Publication2014
AuthorsSuvà, ML, Rheinbay, E, Gillespie, SM, Patel, AP, Wakimoto, H, Rabkin, SD, Riggi, N, Chi, AS, Cahill, DP, Nahed, BV, Curry, WT, Martuza, RL, Rivera, MN, Rossetti, N, Kasif, S, Beik, S, Kadri, S, Tirosh, I, Wortman, I, Shalek, AK, Rozenblatt-Rosen, O, Regev, A, Louis, DN, Bernstein, BE
Date Published2014 Apr 24
KeywordsBasic Helix-Loop-Helix Transcription Factors, Brain Neoplasms, Cell Differentiation, Cell Line, Tumor, Cells, Cultured, Co-Repressor Proteins, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Glioblastoma, Humans, Neoplastic Stem Cells, Nerve Tissue Proteins, Regulatory Elements, Transcriptional, Transcription Factors

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:


Alternate JournalCell
PubMed ID24726434
PubMed Central IDPMC4004670
Grant ListU54 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