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

By M. Suvà, Esther Rheinbay, Shawn M. Gillespie, Anoop P. Patel, H. Wakimoto, S. Rabkin, Nicolò Riggi, A. Chi, D. Cahill, B. Nahed and 14 more. Cell, 2014

887 citations recorded by the source corpus.

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, 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 novel 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.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/857b1956d6eceb4674471b54d3ba55e9e88110be

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Citations in the corpus

An integrative model of cellular states, plasticity and genetics for glioblastoma (2019, neutral): “It also remains challenging to dissect the extent to which unidirectional hierarchies or more reversible state transitions govern glioblastoma and GSC biology (Suvà et al., 2014).”
Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma (2014, background): “each tumor (colored bars): cell cycle, transcriptional targets of POU3F2, SOX2, SALL2, OLIG2 (core TF) (43), NFI transcriptional targets (NFI) (42), and the proneural (PN), classical (CL), mesenchymal (MES) and neural (N) subtypes defined by the Cancer Genome Atlas (21).”
Pioneer Transcription Factors Target Partial DNA Motifs on Nucleosomes to Initiate Reprogramming (2015, positive): “Various examples have been reported on the overexpression of bHLH factors in cancer, including c-Myc,Tal1, andOlig2 (Lin et al., 2012; Nie et al., 2012; Palii et al., 2011; Sanda et al., 2012; Suvà et al., 2014).”
Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma (2016, positive): “Interestingly, SOX2 and OLIG2 have been described as neurodevelopmental transcription factors being essential for GBM propagation (Suva et al., 2014).”
Single-Cell RNA-Seq Analysis of Infiltrating Neoplastic Cells at the Migrating Front of Human Glioblastoma (2017, positive): “Notably, SOX2 has been reported as a marker of glioma stem cells, along with genes POU3F2, OLIG2 and SALL2 (Suvà et al., 2014), while SOX9 has been shown to correlate with poor clinical outcome (Wang et al., 2012b).”
Cancer stem cells in glioblastoma (2015, methodology): “…or structural proteins essential for normalNSPC function alsomark gliomaCSCs, including SOX2 (Hemmati et al. 2003), NANOG (BenPorath et al. 2008; Suva et al. 2014), OLIG2 (Ligon et al. 2007), MYC (Kim et al. 2010), MUSASHI1 (Hemmati et al. 2003), BMI1 (Hemmati et al. 2003), NESTIN (Tunici et…”