Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells.
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:
Duke Scholars
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Related Subject Headings
- Transcription Factors
- Regulatory Elements, Transcriptional
- Oligodendrocyte Transcription Factor 2
- Nerve Tissue Proteins
- Neoplastic Stem Cells
- Humans
- Glioblastoma
- Gene Expression Regulation, Neoplastic
- Epigenesis, Genetic
- Developmental Biology
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Transcription Factors
- Regulatory Elements, Transcriptional
- Oligodendrocyte Transcription Factor 2
- Nerve Tissue Proteins
- Neoplastic Stem Cells
- Humans
- Glioblastoma
- Gene Expression Regulation, Neoplastic
- Epigenesis, Genetic
- Developmental Biology