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Science (New York, N.Y.)
Jun 20, 2014;344 (6190): 1396-401.

Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma.

Anoop P Patel, Itay Tirosh, John J Trombetta, Alex K Shalek, Shawn M Gillespie, Hiroaki Wakimoto, Daniel P Cahill, Brian V Nahed, William T Curry, Robert L Martuza, David N Louis, Orit Rozenblatt-Rosen, Mario L Suvà, Aviv Regev, Bradley E Bernstein
Author Information
  1. Anoop P Patel: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, 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 Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA. Howard Hughes Medical Institute Chevy Chase, MD 20815, USA.
  2. Itay Tirosh: Broad Institute of Harvard and Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA.
  3. John J Trombetta: Broad Institute of Harvard and Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA.
  4. Alex K Shalek: Broad Institute of Harvard and Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA.
  5. Shawn M Gillespie: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Broad Institute of Harvard and Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA. Howard Hughes Medical Institute Chevy Chase, MD 20815, USA.
  6. Hiroaki Wakimoto: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  7. Daniel P Cahill: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  8. Brian V Nahed: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  9. William T Curry: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  10. Robert L Martuza: Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  11. David N Louis: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
  12. Orit Rozenblatt-Rosen: Broad Institute of Harvard and Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA.
  13. Mario L Suvà: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Broad Institute of Harvard and Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA. bernstein.bradley@mgh.harvard.edu aregev@broadinstitute.org suva.mario@mgh.harvard.edu.
  14. Aviv Regev: Broad Institute of Harvard and Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA. Howard Hughes Medical Institute Chevy Chase, MD 20815, USA. Department of Biology, MIT, Cambridge, MA 02139, USA. bernstein.bradley@mgh.harvard.edu aregev@broadinstitute.org suva.mario@mgh.harvard.edu.
  15. Bradley E Bernstein: Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Broad Institute of Harvard and Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA. Howard Hughes Medical Institute Chevy Chase, MD 20815, USA. bernstein.bradley@mgh.harvard.edu aregev@broadinstitute.org suva.mario@mgh.harvard.edu.
PMID: 24925914 DOI: 10.1126/science.1254257

Abstract

Human cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states, but current models do not adequately reflect tumor composition in patients. We used single-cell RNA sequencing (RNA-seq) to profile 430 cells from five primary glioblastomas, which we found to be inherently variable in their expression of diverse transcriptional programs related to oncogenic signaling, proliferation, complement/immune response, and hypoxia. We also observed a continuum of stemness-related expression states that enabled us to identify putative regulators of stemness in vivo. Finally, we show that established glioblastoma subtype classifiers are variably expressed across individual cells within a tumor and demonstrate the potential prognostic implications of such intratumoral heterogeneity. Thus, we reveal previously unappreciated heterogeneity in diverse regulatory programs central to glioblastoma biology, prognosis, and therapy.

Associated Data

GEO | GSE57872

References

Nature. 2006 Dec 7;444(7120):756-60 [PMID: 17051156]
Cancer Cell. 2009 Jun 2;15(6):501-13 [PMID: 19477429]
Sci Rep. 2014 Feb 27;4:4223 [PMID: 24573247]
J Neurosci. 2008 Jan 2;28(1):264-78 [PMID: 18171944]
Nature. 2004 Nov 18;432(7015):396-401 [PMID: 15549107]
Cell. 2010 May 14;141(4):583-94 [PMID: 20478252]
Nature. 2011 Apr 7;472(7341):90-4 [PMID: 21399628]
Genes Dev. 2013 Aug 15;27(16):1769-86 [PMID: 23964093]
Nature. 2012 Aug 23;488(7412):522-6 [PMID: 22854781]
Cancer Cell. 2011 Dec 13;20(6):810-7 [PMID: 22137795]
Annu Rev Pathol. 2014;9:1-25 [PMID: 23937436]
Science. 2007 Oct 12;318(5848):287-90 [PMID: 17872411]
Genome Biol. 2009;10(3):R25 [PMID: 19261174]
Cancer Cell. 2006 May;9(5):391-403 [PMID: 16697959]
Cancer Cell. 2010 Jan 19;17(1):98-110 [PMID: 20129251]
Cancer Cell. 2010 May 18;17(5):510-22 [PMID: 20399149]
Science. 2008 Aug 22;321(5892):1095-100 [PMID: 18719287]
Cell Rep. 2014 Mar 27;6(6):1085-1095 [PMID: 24613353]
N Engl J Med. 2012 Mar 8;366(10):883-892 [PMID: 22397650]
Science. 2008 Sep 26;321(5897):1807-12 [PMID: 18772396]
Neuro Oncol. 2012 Feb;14(2):132-44 [PMID: 22067563]
Nat Med. 2011 Aug 28;17(9):1086-93 [PMID: 21873988]
Science. 2014 Jan 3;343(6166):72-6 [PMID: 24310612]
Nat Neurosci. 2014 Jan;17(1):131-43 [PMID: 24316888]
Nature. 2010 Dec 9;468(7325):829-33 [PMID: 21102433]
Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4009-14 [PMID: 23412337]
Cell. 2011 Jan 21;144(2):296-309 [PMID: 21241896]
Nature. 2010 Dec 9;468(7325):824-8 [PMID: 21102434]
Cell. 2014 Apr 24;157(3):580-94 [PMID: 24726434]
Nat Biotechnol. 2012 Aug;30(8):777-82 [PMID: 22820318]
Nat Genet. 2013 Jun;45(6):580-5 [PMID: 23715323]
Cancer Cell. 2013 Sep 9;24(3):331-46 [PMID: 23993863]
BMC Bioinformatics. 2011 Aug 04;12:323 [PMID: 21816040]
Cell. 2013 Oct 10;155(2):462-77 [PMID: 24120142]
N Engl J Med. 2014 Feb 20;370(8):699-708 [PMID: 24552317]
Science. 2012 Aug 10;337(6095):730-5 [PMID: 22855427]
Nature. 2013 Sep 19;501(7467):355-64 [PMID: 24048068]
Nature. 2012 Aug 23;488(7412):527-30 [PMID: 22854777]
Nature. 2013 Jun 13;498(7453):236-40 [PMID: 23685454]
J Surg Oncol. 2003 Jan;82(1):57-64 [PMID: 12501169]
Physiol Genomics. 2003 May 13;13(3):249-62 [PMID: 12644598]
Neoplasia. 2011 May;13(5):461-71 [PMID: 21532887]
Proc Natl Acad Sci U S A. 2011 Mar 15;108(11):4274-80 [PMID: 21262804]
Nature. 2010 Oct 28;467(7319):1114-7 [PMID: 20981102]
Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):270-5 [PMID: 23248284]
N Engl J Med. 2005 Mar 10;352(10):987-96 [PMID: 15758009]
Nature. 2013 Sep 19;501(7467):328-37 [PMID: 24048065]

Grants

  1. /Howard Hughes Medical Institute
  2. R25NS065743/NINDS NIH HHS
  3. P50 CA165962/NCI NIH HHS
  4. R25 NS065743/NINDS NIH HHS
  5. U54 HG006991/NHGRI NIH HHS
  6. U24 CA180922/NCI NIH HHS
  7. R01 NS032677/NINDS NIH HHS

MeSH Term

Brain Neoplasms
Gene Expression Profiling
Genetic Variation
Glioblastoma
Humans
Prognosis
RNA, Messenger
Sequence Analysis, RNA
Single-Cell Analysis

Chemicals

RNA, Messenger
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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