Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq

Andrew S Venteicher; Itay Tirosh; Christine Hebert; Keren Yizhak; Cyril Neftel; Mariella G Filbin; Volker Hovestadt; Leah E Escalante; McKenzie L Shaw; Christopher Rodman; Shawn M Gillespie; Danielle Dionne; Christina C Luo; Hiranmayi Ravichandran; Ravindra Mylvaganam; Christopher Mount; Maristela L Onozato; Brian V Nahed; Hiroaki Wakimoto; William T Curry; A John Iafrate; Miguel N Rivera; Matthew P Frosch; Todd R Golub; Priscilla K Brastianos; Gad Getz; Anoop P Patel; Michelle Monje; Daniel P Cahill; Orit Rozenblatt-Rosen; David N Louis; Bradley E Bernstein; Aviv Regev; Mario L Suvà

doi:10.1126/science.aai8478

Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq

Science. 2017 Mar 31;355(6332):eaai8478. doi: 10.1126/science.aai8478.

Authors

Andrew S Venteicher^{1

2

3}, Itay Tirosh⁴, Christine Hebert^{1

2}, Keren Yizhak^{1

2}, Cyril Neftel^{1

2

5}, Mariella G Filbin^{1

2

6}, Volker Hovestadt^{1

2}, Leah E Escalante^{1

2}, McKenzie L Shaw^{1

2}, Christopher Rodman², Shawn M Gillespie¹, Danielle Dionne², Christina C Luo¹, Hiranmayi Ravichandran¹, Ravindra Mylvaganam¹, Christopher Mount⁷, Maristela L Onozato¹, Brian V Nahed³, Hiroaki Wakimoto³, William T Curry³, A John Iafrate¹, Miguel N Rivera^{1

2}, Matthew P Frosch¹, Todd R Golub^{2

6

8}, Priscilla K Brastianos⁹, Gad Getz^{1

2}, Anoop P Patel³, Michelle Monje⁷, Daniel P Cahill³, Orit Rozenblatt-Rosen², David N Louis¹, Bradley E Bernstein^{1

2}, Aviv Regev^{4

8

10}, Mario L Suvà^{11

2}

Affiliations

¹ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
² Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
³ Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
⁴ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. suva.mario@mgh.harvard.edu aregev@broadinstitute.org tirosh@broadinstitute.org.
⁵ Institute of Pathology, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
⁶ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Cancer Center, Boston, MA 02215, USA.
⁷ Departments of Neurology, Neurosurgery, Pediatrics and Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁸ Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
⁹ Departments of Medicine and Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
¹⁰ Koch Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
¹¹ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. suva.mario@mgh.harvard.edu aregev@broadinstitute.org tirosh@broadinstitute.org.

Abstract

Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses.

Publication types

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

MeSH terms

Brain Neoplasms / classification
Brain Neoplasms / genetics*
Brain Neoplasms / pathology*
Cell Lineage
Glioma / classification
Glioma / genetics*
Glioma / pathology*
Humans
Isocitrate Dehydrogenase / genetics*
Macrophages
Microglia / metabolism
Microglia / pathology
Neoplasm Grading
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
Principal Component Analysis
Sequence Analysis, RNA
Single-Cell Analysis
Tumor Microenvironment*

Substances

Isocitrate Dehydrogenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding