title: Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells.
abstract: 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:
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: suva.mario@mgh.harvard.edu.
authors.forename: Mario L
authors.initials: ML
authors.lastname: Suvà
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Rheinbay
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Gillespie
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Anoop P
authors.initials: AP
authors.lastname: Patel
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Rabkin
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Nicolo
authors.initials: N
authors.lastname: Riggi
authors.affiliation: Divisions of Neuro-Oncology and Hematology/Oncology and Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chi
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Cahill
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Brian V
authors.initials: BV
authors.lastname: Nahed
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Curry
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Martuza
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Rivera
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Nikki
authors.initials: N
authors.lastname: Rossetti
authors.affiliation: Bioinformatics Program, Boston University, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Kasif
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Beik
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Sabah
authors.initials: S
authors.lastname: Kadri
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Itay
authors.initials: I
authors.lastname: Tirosh
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Ivo
authors.initials: I
authors.lastname: Wortman
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Alex K
authors.initials: AK
authors.lastname: Shalek
authors.affiliation: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Orit
authors.initials: O
authors.lastname: Rozenblatt-Rosen
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02140, USA.
authors.forename: Aviv
authors.initials: A
authors.lastname: Regev
authors.affiliation: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: bernstein.bradley@mgh.harvard.edu.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D056970:Co-Repressor Proteins / Q000378:metabolism; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D050436:Regulatory Elements, Transcriptional; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D056970:Co-Repressor Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D014157:Transcription Factors; C405708:OLIG2 protein, human; C000589202:Rcor2 protein, human
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