Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma.
Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and epigenetic programs in which cancer stem cells (CSCs) can drive tumour growth and give rise to differentiated progeny. Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2 mutant human oligodendrogliomas by RNA sequencing (RNA-seq) and reconstruct their developmental programs from genome-wide expression signatures. We infer that most cancer cells are differentiated along two specialized glial programs, whereas a rare subpopulation of cells is undifferentiated and associated with a neural stem cell expression program. Cells with expression signatures for proliferation are highly enriched in this rare subpopulation, consistent with a model in which CSCs are primarily responsible for fuelling the growth of oligodendroglioma in humans. Analysis of copy number variation (CNV) shows that distinct CNV sub-clones within tumours display similar cellular hierarchies, suggesting that the architecture of oligodendroglioma is primarily dictated by developmental programs. Subclonal point mutation analysis supports a similar model, although a full phylogenetic tree would be required to definitively determine the effect of genetic evolution on the inferred hierarchies. Our single-cell analyses provide insight into the cellular architecture of oligodendrogliomas at single-cell resolution and support the cancer stem cell model, with substantial implications for disease management.
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Itay
I
Tirosh
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.|Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Andrew S
AS
Venteicher
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Christine
C
Hebert
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Leah E
LE
Escalante
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Anoop P
AP
Patel
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Keren
K
Yizhak
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Jonathan M
JM
Fisher
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Christopher
C
Rodman
Departments of Neurology, Neurosurgery, Pediatrics and Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
Christopher
C
Mount
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Cancer Center, Boston, Massachusetts 02215, USA.
Mariella G
MG
Filbin
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Cyril
C
Neftel
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Niyati
N
Desai
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Jackson
J
Nyman
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Benjamin
B
Izar
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Christina C
CC
Luo
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
Joshua M
JM
Francis
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Aanand A
AA
Patel
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Maristela L
ML
Onozato
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Nicolo
N
Riggi
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Kenneth J
KJ
Livak
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Dave
D
Gennert
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Rahul
R
Satija
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Brian V
BV
Nahed
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
William T
WT
Curry
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Robert L
RL
Martuza
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Ravindra
R
Mylvaganam
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
A John
AJ
Iafrate
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Matthew P
MP
Frosch
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Cancer Center, Boston, Massachusetts 02215, USA.|Howard Hughes Medical Institute, Koch Institute, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.
Todd R
TR
Golub
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Miguel N
MN
Rivera
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Gad
G
Getz
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
Orit
O
Rozenblatt-Rosen
Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Daniel P
DP
Cahill
Departments of Neurology, Neurosurgery, Pediatrics and Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
Michelle
M
Monje
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Bradley E
BE
Bernstein
Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
David N
DN
Louis
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Howard Hughes Medical Institute, Koch Institute, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.
Aviv
A
Regev
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.|Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Mario L
ML
Suvà
D002454:Cell Differentiation; D049109:Cell Proliferation; D056915:DNA Copy Number Variations / Q000235:genetics; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009837:Oligodendroglioma / Q000235:genetics* / Q000473:pathology*; D010802:Phylogeny; D017354:Point Mutation; D017423:Sequence Analysis, RNA; D059010:Single-Cell Analysis
C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human