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.
Journal article
An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma
Cell, Vol.178(4), pp.835-849.e21
08/Aug/2019
Abstract
Details
- Title
- An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma
- Creators
- Cyril Neftel (null) - Massachusetts General HospitalJulie Laffy (null) - 972WIS_INST___9Mariella G. Filbin (null) - Massachusetts General HospitalToshiro Hara (null) - Massachusetts General HospitalMarni E. Shore (null) - Massachusetts General HospitalGilbert J. Rahme (null) - Massachusetts General HospitalAlyssa R. Richman (null) - Massachusetts General HospitalDana Silverbush (null) - Massachusetts General HospitalMcKenzie L. Shaw (null) - Massachusetts General HospitalChristine M. Hebert (null) - Massachusetts General HospitalJohn Dewitt (null) - Massachusetts General HospitalSimon Gritsch (null) - Massachusetts General HospitalElizabeth M. Perez (null) - Massachusetts General HospitalL. Nicolas Gonzalez Castro (null) - Massachusetts General HospitalXiaoyang Lan (null) - Massachusetts General HospitalNicholas Druck (null) - Massachusetts General HospitalChristopher Rodman (null) - Massachusetts General HospitalDanielle Dionne (null) - Broad InstituteAlexander Kaplan (null) - Massachusetts General HospitalMia S. Bertalan (null) - Massachusetts General HospitalJulia Small (null) - Massachusetts General HospitalKristine Pelton (null) - Brigham and Women's HospitalSarah Becker (null) - Brigham and Women's HospitalDennis Bonal (null) - Dana-Farber Cancer InstituteQuang-De Nguyen (null) - Dana-Farber Cancer InstituteRachel L. Servis (null) - Massachusetts General HospitalJeremy M. Fung (null) - Massachusetts General HospitalRavindra Mylvaganam (null) - Massachusetts General HospitalLisa Mayr (null) - Dana-Farber Cancer InstituteJohannes Gojo (null) - Medical University of ViennaChristine Haberler (null) - Medical University of ViennaRene Geyeregger (null) - Medical University of ViennaThomas Czech (null) - Medical University of ViennaIrene Slavc (null) - Medical University of ViennaBrian Nahed (null) - Massachusetts General HospitalWilliam T. Curry (null) - Massachusetts General HospitalBob S. Carter (null) - Massachusetts General HospitalHiroaki Wakimoto (null) - Massachusetts General HospitalPriscilla K. Brastianos (null) - Massachusetts General HospitalTracy T. Batchelor (null) - Massachusetts General HospitalAnat Stemmer-Rachamimov (null) - Massachusetts General HospitalMaria Martinez-Lage (null) - Massachusetts General HospitalMatthew P. Frosch (null) - Massachusetts General HospitalIvan Stamenkovic (null) - University Hospital of LausanneNicolo Riggi (null) - University Hospital of LausanneEsther Rheinbay (null) - Massachusetts General HospitalMichelle Monje (null) - Stanford UniversityOrit Rozenblatt-Rosen (null) - Broad InstituteDaniel P. Cahill (null) - Massachusetts General HospitalAnoop P. Patel (null) - University of WashingtonTony Hunter (null) - Salk Institute for Biological StudiesInder M. Verma (null) - Salk Institute for Biological StudiesKeith L. Ligon (null) - Broad InstituteDavid N. Louis (null) - Massachusetts General HospitalAviv Regev (null) - Broad InstituteBradley E. Bernstein (null) - Massachusetts General HospitalItay Tirosh (null) - 972WIS_INST___122Mario L. Suva (null) - Massachusetts General Hospital
- Resource Type
- Journal article
- Publication Details
- Cell, Vol.178(4), pp.835-849.e21; 08/Aug/2019
- Number of pages
- 36
- Language
- English
- DOI
- https://doi.org/10.1016/j.cell.2019.06.024
- Grant note
- We thank Ania Hupaloska and Sébastien Perroud for help with graphics. This work was supported by grants to M.L. Suvà from the Sontag Foundation, the Howard Goodman Fellowship, the Merkin Institute Fellowship, the Wang Family Fund, the Smith Family Foundation, the Chan-Zuckerberg Initiative, the Alex’s Lemonade Stand Foundation, the V Foundation for Cancer Research, and The Swiss National Science Foundation Sinergia grant to M.L.Suvà. and I.S. I.T. is the incumbent of the Dr. Celia Zwillenberg-Fridman and Dr. Lutz Zwillenberg Career Development Chair, and was supported by the Zuckerman STEM Leadership Program, the Human Frontiers Science Program, the Mexican friends new generation, and the Benoziyo Endowment Fund. M.G.F. was supported by a Career Award for Medical Scientist from Burroughs Wellcome Fund and K12 Paul Calabresi Career Award for Clinical Oncology (K12CA090354). C.N. was supported by the Placide Nicod Foundation. T.Hara was supported by Grant-in-Aid for JSPS Fellows from the Japan Society for the Promotion of Science. A.R. was supported by funds from the Howard Hughes Medical Institute, the Klarman Cell Observatory, STARR cancer consortium, NCI grants 1U24CA180922 and R33CA202820, the Koch Institute Support (core) (P30CA14051) from the National Cancer Institute, the Ludwig Center and the Broad Institute. A.R. is a scientific advisory board member for ThermoFisher Scientific, Syros Pharmaceuticals and Driver Group. A.P.P. was supported by a Career Award for Medical Scientist from Burroughs Wellcome Fund. D.P.C. is supported by the BWF Career Award in the Medical Sciences, and Tawingo Chair Fund and has received consulting fees from Lilly and Merck (unrelated to this work). B.E.B. was supported by the NIH Common Fund and National Cancer Institute (DP1CA216873), the American Cancer Society, the Ludwig Center at Harvard Medical School, and the Bernard and Mildred Kayden MGH Research Institute Chair. B.E.B. is an advisor and equity holder for Fulcrum Therapeutics, 1CellBio, HiFiBio, and Arsenal Biosciences; is an advisor for Cell Signaling Technologies; and has equity in Nohla Therapeutics. Flow-cytometry and sorting services at MGH were supported by NIH shared instrumentation grants 1S10RR023440-01A1 and P30CA014195. Flow-cytometry and sorting services at the Salk Institute were supported by NIH grant S10-OD023689. I.M.V. and T.Hunter were supported by NIH grant R01CA195613 and the Helmsley Center for Genomic Medicine.
- Record Identifier
- 993264042803596
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