Person: Beik, Samantha Petrillo
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Publication Reconstructing and Reprogramming the Tumor-Propagating Potential of Glioblastoma Stem-like Cells
(Elsevier BV, 2014) Suva, Mario; Rheinbay, Esther; Gillespie, Shawn M.; Patel, Anoop Premswaroop; Wakimoto, Hiroaki; Rabkin, Samuel; Riggi, Nicolo; Chi, Anthony Wei Shine; Cahill, Daniel; Nahed, Brian; Curry, William; Martuza, Robert; Rivera, Miguel; Rossetti, Nikki; Kasif, Simon; Beik, Samantha Petrillo; Kadri, Sabah; Tirosh, Itay; Wortman, Ivo; Shalek, Alex K.; Rozenblatt-Rosen, Orit; Regev, Aviv; Louis, David; Bernstein, BradleyDevelopmental 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.