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

Mario L Suvà; Esther Rheinbay; Shawn M Gillespie; Anoop P Patel; Hiroaki Wakimoto; Samuel D Rabkin; Nicolo Riggi; Andrew S Chi; Daniel P Cahill; Brian V Nahed; William T Curry; Robert L Martuza; Miguel N Rivera; Nikki Rossetti; Simon Kasif; Samantha Beik; Sabah Kadri; Itay Tirosh; Ivo Wortman; Alex K Shalek; Orit Rozenblatt-Rosen; Aviv Regev; David N Louis; Bradley E Bernstein

doi:10.1016/j.cell.2014.02.030

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

Cell. 2014 Apr 24;157(3):580-94. doi: 10.1016/j.cell.2014.02.030. Epub 2014 Apr 10.

Authors

Mario L Suvà¹, Esther Rheinbay², Shawn M Gillespie², Anoop P Patel³, Hiroaki Wakimoto⁴, Samuel D Rabkin⁴, Nicolo Riggi⁵, Andrew S Chi⁶, Daniel P Cahill⁴, Brian V Nahed⁴, William T Curry⁴, Robert L Martuza⁴, Miguel N Rivera⁵, Nikki Rossetti⁵, Simon Kasif⁷, Samantha Beik⁸, Sabah Kadri⁸, Itay Tirosh⁸, Ivo Wortman⁸, Alex K Shalek⁹, Orit Rozenblatt-Rosen⁸, Aviv Regev¹⁰, David N Louis¹¹, Bradley E Bernstein¹²

Affiliations

¹ 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.
² 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.
³ Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA; Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁴ Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁵ 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.
⁶ Divisions of Neuro-Oncology and Hematology/Oncology and Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁷ Bioinformatics Program, Boston University, Boston, MA 02215, USA; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
⁸ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁹ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
¹⁰ 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.
¹¹ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹² 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.

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:

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Basic Helix-Loop-Helix Transcription Factors / metabolism
Brain Neoplasms / genetics*
Brain Neoplasms / metabolism
Brain Neoplasms / pathology*
Cell Differentiation
Cell Line, Tumor
Cells, Cultured
Co-Repressor Proteins / metabolism
Epigenesis, Genetic
Gene Expression Regulation, Neoplastic
Glioblastoma / genetics*
Glioblastoma / metabolism
Glioblastoma / pathology*
Humans
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology*
Nerve Tissue Proteins / metabolism
Oligodendrocyte Transcription Factor 2
Regulatory Elements, Transcriptional
Transcription Factors / metabolism

Substances

Basic Helix-Loop-Helix Transcription Factors
Co-Repressor Proteins
Nerve Tissue Proteins
OLIG2 protein, human
Oligodendrocyte Transcription Factor 2
Rcor2 protein, human
Transcription Factors

Associated data

GEO/GSE54792

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding