title: Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma.
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.
authors.affiliation: 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.
authors.forename: Anoop P
authors.initials: AP
authors.lastname: Patel
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA.
authors.forename: Itay
authors.initials: I
authors.lastname: Tirosh
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Trombetta
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA.
authors.forename: Alex K
authors.initials: AK
authors.lastname: Shalek
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 Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA. Howard Hughes Medical Institute Chevy Chase, MD 20815, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Gillespie
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: 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.
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.affiliation: Broad Institute of Harvard and Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA.
authors.forename: Orit
authors.initials: O
authors.lastname: Rozenblatt-Rosen
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 Massachusetts Institute of Techonology (MIT), Cambridge, MA 02142, USA. bernstein.bradley@mgh.harvard.edu aregev@broadinstitute.org suva.mario@mgh.harvard.edu.
authors.forename: Mario L
authors.initials: ML
authors.lastname: Suvà
authors.affiliation: 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.
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. 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.
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
mesh_terms: D001932:Brain Neoplasms / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D020869:Gene Expression Profiling; D014644:Genetic Variation; D005909:Glioblastoma / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics*; D017423:Sequence Analysis, RNA / Q000379:methods; D059010:Single-Cell Analysis / Q000379:methods
chemical_list: D012333:RNA, Messenger