Reconstructing and Reprogramming the Tumor-Propagating Potential of Glioblastoma Stem-like Cells

Cell (Impact Factor: 32.24). 04/2014; 157(3). DOI: 10.1016/j.cell.2014.02.030
Source: PubMed


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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    • "GBMs contain glioma stem cells (GSCs) that have a phenotype similar to adult human neural stem cells (ahNSCs) [1]. These cells are drivers of GBM propagation [2] [3] and therapy resistance [4], and are thus believed to be responsible for the invariable recurrence of the tumor. When cultured under serum-free, growth factor-enriched conditions, both ahNSCs and GSCs grow in spherical aggregates of cells known as neuro-or tumorspheres. "
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    ABSTRACT: Evidence indicates that the growth of glioblastoma (GBM), the most common and malignant primary brain cancer, is driven by glioma stem cells (GSCs) resistant to current treatment. As Wnt-signaling is pivotal in stem cell maintenance, we wanted to explore its role in GSCs with the objective of finding distinct signaling mechanisms that could serve as potential therapeutic targets. We compared gene expression in GSCs (n=9) and neural stem cells from the adult human brain (ahNSC; n=3) to identify dysregulated genes in the Wnt signaling pathway. This identified a six-gene Wnt signature present in all nine primary GSC cultures, and the combined expression of three of these genes (SFRP1, SFRP4 and FZD7) reduced median survival of glioma patients from 38 to 17 months. Treatment with recombinant SFRP1 protein in primary cell cultures downregulated nuclear β-catenin and decreased in vitro proliferation and sphere formation in a dose-dependent manner. Furthermore, expressional and functional analysis of SFRP1-treated GSCs revealed that SFRP1 halts cell cycling and induces apoptosis. These observations demonstrate that Wnt signaling is dysregulated in GSC, and that inhibition of the Wnt pathway could serve as a therapeutic strategy in the treatment of GBM.
    Preview · Article · Dec 2015 · Experimental Cell Research
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    • "These exclusively intracranial and lethal tumors have recently been subdivided into at least four molecular forms, including: proneural, neural, classical and mesenchymal GBM. Each of these subtypes is associated with a unique mutational and gene expression signatures, which are indicative of divergent pathogenetic mechanisms [5] [6]. This diversity also includes distinctive profiles of genes related to coagulation and fibrinolytic systems (coagulome), many of which are expressed by cancer cells ectopically (e.g., FVII) [7]. "
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    ABSTRACT: Glioblastoma multiforme (GBM) is an aggressive form of glial brain tumors, associated with angiogenesis, thrombosis, and upregulation of tissue factor (TF), the key cellular trigger of coagulation and signaling. Since TF is upregulated by oncogenic mutations occurring in different subsets of human brain tumors we investigated whether TF contributes to tumourigenesis driven by oncogenic activation of EGFR (EGFRvIII) and RAS pathways in the brain. Here we show that TF expression correlates with poor prognosis in glioma, but not in GBM. In situ, the TF protein expression is heterogeneously expressed in adult and pediatric gliomas. GBM cells harboring EGFRvIII (U373vIII) grow aggressively as xenografts in SCID mice and their progression is delayed by administration of monoclonal antibodies blocking coagulant (CNTO 859) and signaling (10H10) effects of TF in vivo. Mice in which TF gene is disrupted in the neuroectodermal lineage exhibit delayed progression of spontaneous brain tumors driven by oncogenic N-ras and SV40 large T antigen (SV40LT) expressed under the control of sleeping beauty transposase. Reduced host TF levels in low-TF/SCID hypomorphic mice mitigated growth of glioma subcutaneously but not in the brain. Thus, we suggest that tumor-associated TF may serve as therapeutic target in the context of oncogene-driven disease progression in a subset of glioma.
    Full-text · Article · Oct 2014 · Biochemical and Biophysical Research Communications
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    • "Sox member Finding Reference SOX2-Glioblastoma sustains stemness properties and tumorigenicity [55] Transcriptional regulation mediated by TGF-β [56] Genetic and Epigenetic modifications [53] Factor responsible for glioblastoma stem cells reprogramming [57] SOX2-medulloblastoma Sustains stemness properties but not involved in tumor survival [78] SOX2-oligodendroglioma Required to maintain stemness properties and tumorigenicity [71] SOX4-Glioblastoma Sustains stemness regulated by TGF-β and modulating SOX2 [56] induces the expression of SOX2 forming cooperative complexes with OCT-4 that bind to the SOX2 promoter [56]. In addition to their function regulating GSCs, combined high expression of OCT-4, SOX4 and SOX2 confers lower patient survival and correlates with p53-mutat- ed status in GBM cases [87], highlighting the clinical relevance of this axis. "
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    ABSTRACT: SOX genes are developmental regulators with functions in the instruction of cell fate and maintenance of progenitor's identity during embryogenesis. They play additional roles during tissue homeostasis and regeneration in adults particularly in the Central Nervous System (CNS). In the last years a growing number of evidences has shown that mutations and dysfunction of SOX factors are implicated in several human diseases, including a variety of cancers. In this review, we will summarize the current knowledge about SOX family in CNS tumors and their role in the origin and maintenance of the subpopulation of cancer stem cells in these tumors.
    Full-text · Article · Jul 2014 · American Journal of Cancer Research
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