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

Mario L. Suvà*, Esther Rheinbay, Shawn M. Gillespie, Anoop P. Patel, Hiroaki Wakimoto, Samuel D. Rabkin, Nicolo Riggi, Andrew S. Chi, Daniel P. Cahill, Brian V. Nahed, William T. Curry, Robert L. Martuza, Miguel N. Rivera, Nikki Rossetti, Simon Kasif, Samantha Beik, Sabah Kadri, Itay Tirosh, Ivo Wortman, Alex K. ShalekOrit Rozenblatt-Rosen, Aviv Regev, David N. Louis, Bradley E. Bernstein

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

457 Scopus citations

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

Original languageEnglish (US)
Pages (from-to)580-594
Number of pages15
JournalCell
Volume157
Issue number3
DOIs
StatePublished - Apr 24 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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