Journal
CELL
Volume 178, Issue 4, Pages 835-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2019.06.024
Keywords
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Categories
Funding
- Sontag Foundation
- Howard Goodman Fellowship
- Merkin Institute Fellowship
- Wang Family Fund
- Smith Family Foundation
- Chan-Zuckerberg Initiative
- Alex's Lemonade Stand Foundation
- V Foundation for Cancer Research
- Swiss National Science Foundation Sinergia grant
- Zuckerman STEM Leadership Program
- Human Frontiers Science Program
- Mexican friends new generation
- Benoziyo Endowment Fund
- Career Award for Medical Scientist from Burroughs Wellcome Fund
- K12 Paul Calabresi Career Award for Clinical Oncology [K12CA090354]
- Placide Nicod Foundation
- Japan Society for the Promotion of Science
- Howard Hughes Medical Institute
- Klarman Cell Observatory
- STARR cancer consortium
- NCI [1U24CA180922, R33CA202820]
- Koch Institute Support (core) from the National Cancer Institute [P30CA14051]
- Ludwig Center
- Broad Institute
- NIH Common Fund
- National Cancer Institute [DP1CA216873]
- American Cancer Society
- Ludwig Center at Harvard Medical School
- Bernard and Mildred Kayden MGH Research Institute Chair
- NIH shared instrumentation grants [1S10RR023440-01A1, P30CA014195]
- NIH [S10-OD023689, R01CA195613]
- Helmsley Center for Genomic Medicine
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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.
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