Reconstructing and Reprogramming the Tumor-Propagating Potential of Glioblastoma Stem-like Cells

Biology Biology
Cancer Cancer
Genomics Genomics
Alex K. Shalek Alex K. Shalek

Suvà et al.▾ Suvà, M. *, Rheinbay, E.*, Gillespie, S.M., Patel, A.P., Chi, A.S., Riggi, N., Wakimoto, H., Rabkin, S.D., Matuza, R.L., Rivera, M.N., Rossetti, N., Beik, S., Kasif, S., Wortman, I., Shalek, A.K., Rozenblatt-Rosen, O., Regev, A., Louis, D.N., and Bernstein, B.E.

Cell , Volume 157

April, 2014


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 tumorpropagating 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.