Cell
Volume 157, Issue 3, 24 April 2014, Pages 580-594
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Article
Reconstructing and Reprogramming the Tumor-Propagating Potential of Glioblastoma Stem-like Cells

https://doi.org/10.1016/j.cell.2014.02.030Get rights and content
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Highlights

  • Distinct epigenetic state enables glioblastoma (GBM) cells to propagate tumors in vivo

  • Four TFs reprogram differentiated GBM cells into tumor-propagating stem-like cells

  • These four TFs are coordinately expressed in stem-like cells in primary human tumors

  • The TF target LSD1 may serve as a therapeutic target in tumor-propagating cells

Summary

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.

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