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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    • "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.
    Biochemical and Biophysical Research Communications 10/2014; 454(2). DOI:10.1016/j.bbrc.2014.10.041 · 2.30 Impact Factor
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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.
    American Journal of Cancer Research 07/2014; 4(4):312-24. · 4.17 Impact Factor
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    • "The cancer stem cell hypothesis predicts that the conversion of highly tumorigenic cancer stem cell to non-stem cell progeny is irreversible. However, there is mounting evidence in several cancers such as colon cancer, glioblastoma, and melanoma that the conversion of cancer stem cells to differentiated progeny is reversible (Charles et al, 2010; Roesch et al, 2010; Schwitalla et al, 2013; Suva et al, 2014). This has been demonstrated in melanoma with JARID1B as a cancer stem cell marker, in the perivascular niche of gliomas with nitric oxide promoting stem cell character, and in colon cancer where inflammation triggers dedifferentiation of non-stem cells to stem cells. "
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    ABSTRACT: Heterogeneity within tumors is becoming increasingly recognized as an important cause of treatment failure in cancer. Two recent studies use fate-mapping and limiting dilution transplantation assays to identify SRY (sex determining region Y)-box 2 (Sox2) as cancer stem-cell marker and driver of cancer stemness. The identification of Sox2 as cancer stem-cell marker and driver of cancer stemness in distinct tumor types suggests that each tumor resembles the hierarchical organization of the tissue from which it arises.
    The EMBO Journal 07/2014; 33(18). DOI:10.15252/embj.201489479 · 10.43 Impact Factor
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