An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma

Cyril Neftel; Julie Laffy; Mariella G Filbin; Toshiro Hara; Marni E Shore; Gilbert J Rahme; Alyssa R Richman; Dana Silverbush; McKenzie L Shaw; Christine M Hebert; John Dewitt; Simon Gritsch; Elizabeth M Perez; L Nicolas Gonzalez Castro; Xiaoyang Lan; Nicholas Druck; Christopher Rodman; Danielle Dionne; Alexander Kaplan; Mia S Bertalan; Julia Small; Kristine Pelton; Sarah Becker; Dennis Bonal; Quang-De Nguyen; Rachel L Servis; Jeremy M Fung; Ravindra Mylvaganam; Lisa Mayr; Johannes Gojo; Christine Haberler; Rene Geyeregger; Thomas Czech; Irene Slavc; Brian V Nahed; William T Curry; Bob S Carter; Hiroaki Wakimoto; Priscilla K Brastianos; Tracy T Batchelor; Anat Stemmer-Rachamimov; Maria Martinez-Lage; Matthew P Frosch; Ivan Stamenkovic; Nicolo Riggi; Esther Rheinbay; Michelle Monje; Orit Rozenblatt-Rosen; Daniel P Cahill; Anoop P Patel; Tony Hunter; Inder M Verma; Keith L Ligon; David N Louis; Aviv Regev; Bradley E Bernstein; Itay Tirosh; Mario L Suvà

doi:10.1016/j.cell.2019.06.024

An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma

Cell. 2019 Aug 8;178(4):835-849.e21. doi: 10.1016/j.cell.2019.06.024. Epub 2019 Jul 18.

Authors

Cyril Neftel¹, Julie Laffy², Mariella G Filbin³, Toshiro Hara⁴, Marni E Shore⁵, Gilbert J Rahme⁵, Alyssa R Richman⁵, Dana Silverbush⁵, McKenzie L Shaw³, Christine M Hebert⁵, John Dewitt⁵, Simon Gritsch⁵, Elizabeth M Perez⁵, L Nicolas Gonzalez Castro⁶, Xiaoyang Lan⁵, Nicholas Druck⁷, Christopher Rodman⁷, Danielle Dionne⁸, Alexander Kaplan⁹, Mia S Bertalan⁹, Julia Small¹⁰, Kristine Pelton¹¹, Sarah Becker¹¹, Dennis Bonal¹², Quang-De Nguyen¹², Rachel L Servis⁷, Jeremy M Fung⁷, Ravindra Mylvaganam⁷, Lisa Mayr¹², Johannes Gojo¹³, Christine Haberler¹⁴, Rene Geyeregger¹⁵, Thomas Czech¹⁶, Irene Slavc¹³, Brian V Nahed¹⁰, William T Curry¹⁰, Bob S Carter¹⁰, Hiroaki Wakimoto¹⁰, Priscilla K Brastianos⁹, Tracy T Batchelor⁹, Anat Stemmer-Rachamimov⁷, Maria Martinez-Lage⁷, Matthew P Frosch⁷, Ivan Stamenkovic¹⁷, Nicolo Riggi¹⁷, Esther Rheinbay¹⁸, Michelle Monje¹⁹, Orit Rozenblatt-Rosen⁸, Daniel P Cahill¹⁰, Anoop P Patel²⁰, Tony Hunter²¹, Inder M Verma²¹, Keith L Ligon²², David N Louis⁷, Aviv Regev²³, Bradley E Bernstein⁵, Itay Tirosh²⁴, Mario L Suvà²⁵

Affiliations

¹ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Institute of Pathology, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, 1011, Switzerland.
² Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel.
³ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Pediatric Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, MA 02215, USA.
⁴ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁵ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁶ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Departments of Neurology and Radiation Oncology, Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 02114, USA.
⁷ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA.
⁸ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁹ Departments of Neurology and Radiation Oncology, Division of Hematology/Oncology, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 02114, USA.
¹⁰ Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114 USA.
¹¹ Department of Oncologic Pathology, Brigham and Women's Hospital, Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹² Center for Biomedical Imaging in Oncology, Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹³ Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, 1090, Austria.
¹⁴ Institute of Neurology, Medical University of Vienna, Vienna, 1090, Austria.
¹⁵ Children's Cancer Research Institute (CCRI), St. Anna Kinderspital, Medical University of Vienna, Vienna, 1090, Austria.
¹⁶ Department of Neurosurgery, Medical University of Vienna, Vienna, 1090, Austria.
¹⁷ Institute of Pathology, Faculty of Biology and Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, 1011, Switzerland.
¹⁸ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹⁹ Departments of Neurology, Neurosurgery, Pediatrics and Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
²⁰ Department of Neurological Surgery, University of Washington, Seattle, USA.
²¹ Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
²² Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Oncologic Pathology, Brigham and Women's Hospital, Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
²³ Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA 02139, USA.
²⁴ Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 761001, Israel. Electronic address: Itayt@weizmann.ac.il.
²⁵ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: Suva.Mario@mgh.harvard.edu.

Abstract

Diverse genetic, epigenetic, and developmental programs drive glioblastoma, an incurable and poorly understood tumor, but their precise characterization remains challenging. Here, we use an integrative approach spanning single-cell RNA-sequencing of 28 tumors, bulk genetic and expression analysis of 401 specimens from the The Cancer Genome Atlas (TCGA), functional approaches, and single-cell lineage tracing to derive a unified model of cellular states and genetic diversity in glioblastoma. We find that malignant cells in glioblastoma exist in four main cellular states that recapitulate distinct neural cell types, are influenced by the tumor microenvironment, and exhibit plasticity. The relative frequency of cells in each state varies between glioblastoma samples and is influenced by copy number amplifications of the CDK4, EGFR, and PDGFRA loci and by mutations in the NF1 locus, which each favor a defined state. Our work provides a blueprint for glioblastoma, integrating the malignant cell programs, their plasticity, and their modulation by genetic drivers.

Keywords: CDK4; EGFR; NF1; PDGFRA; glioblastoma IDH-wildtype; glioblastoma stem cells; glioblastoma subtypes; lineage tracing; single-cell RNA-sequencing.

Publication types

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

MeSH terms

Adolescent
Aged
Animals
Brain Neoplasms / genetics*
Brain Neoplasms / pathology
Cell Line, Tumor
Cell Lineage / genetics
Cell Plasticity / genetics*
Child
Cohort Studies
Disease Models, Animal
Female
Genetic Heterogeneity
Glioblastoma / genetics*
Glioblastoma / pathology
Heterografts
Humans
Infant
Male
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Middle Aged
Mutation
RNA-Seq
Single-Cell Analysis / methods
Tumor Microenvironment / genetics

Abstract

Publication types

MeSH terms

Grants and funding