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

Cell
Authors
Keywords
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:

Year of Publication
2014
Journal
Cell
Volume
157
Issue
3
Pages
580-94
Date Published
2014 Apr 24
ISSN
1097-4172
URL
DOI
10.1016/j.cell.2014.02.030
PubMed ID
24726434
PubMed Central ID
PMC4004670
Links
Grant list
U54 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