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

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.

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Affiliated Institutions

• Brigham and Women's Hospital US
• Massachusetts General Hospital US
• Harvard University US
• Medical University of Vienna AT
• Boston Children's Hospital US
• Stanford University US
• St Anna Children's Hospital AT
• Dana-Farber Brigham Cancer Center US
• Dana-Farber Cancer Institute US
• Neurological Surgery US
• Salk Institute for Biological Studies US
• Dana-Farber/Boston Children's Cancer and Blood Disorders Center US
• University of Washington US
• University Hospital of Lausanne CH
• Broad Institute US
• Howard Hughes Medical Institute US
• Seattle University US
• Weizmann Institute of Science IL
• Imaging Center US
• Center for Cancer Research US

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