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Science. 2014 Jun 20;344(6190):1396-401. doi: 10.1126/science.1254257. Epub 2014 Jun 12.

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

Author information

1
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
Broad Institute of Harvard and Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA.
3
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.
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.
6
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.
7
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.
8
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.

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.

PMID:
24925914
PMCID:
PMC4123637
DOI:
10.1126/science.1254257
[Indexed for MEDLINE]
Free PMC Article

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