학술논문
Reconstructing and Reprogramming the Tumor-Propagating Potential of Glioblastoma Stem-like Cells.
Document Type
Article
Author
Suvà, Mario?L.; Rheinbay, Esther; Gillespie, Shawn?M.; Patel, Anoop?P.; Wakimoto, Hiroaki; Rabkin, Samuel?D.; Riggi, Nicolo; Chi, Andrew?S.; Cahill, Daniel?P.; Nahed, Brian?V.; Curry, William?T.; Martuza, Robert?L.; Rivera, Miguel?N.; Rossetti, Nikki; Kasif, Simon; Beik, Samantha; Kadri, Sabah; Tirosh, Itay; Wortman, Ivo; Shalek, Alex K.
Source
Subject
*GLIOBLASTOMA multiforme
*STEM cells
*TRANSCRIPTION factors
*CHROMOSOME abnormalities
*CANCER invasiveness
*TUMOR growth
*PHENOTYPES
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Language
ISSN
0092-8674
Abstract
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. PaperClip: Display Omitted [Copyright &y& Elsevier]