Patient-derived models recapitulate heterogeneity of molecular signatures and drug response in pediatric high-grade glioma
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Published:2021-07-02
Issue:1
Volume:12
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
He Chen, Xu Ke, Zhu Xiaoyan, Dunphy Paige S., Gudenas Brian, Lin Wenwei, Twarog Nathaniel, Hover Laura D., Kwon Chang-Hyuk, Kasper Lawryn H., Zhang Junyuan, Li Xiaoyu, Dalton James, Jonchere Barbara, Mercer Kimberly S., Currier Duane G., Caufield WilliamORCID, Wang YingzheORCID, Xie Jia, Broniscer Alberto, Wetmore Cynthia, Upadhyaya Santhosh A., Qaddoumi Ibrahim, Klimo Paul, Boop Frederick, Gajjar Amar, Zhang JinghuiORCID, Orr Brent A.ORCID, Robinson Giles W.ORCID, Monje MichelleORCID, Freeman III Burgess B., Roussel Martine F.ORCID, Northcott Paul A.ORCID, Chen TaoshengORCID, Rankovic Zoran, Wu GangORCID, Chiang JasonORCID, Tinkle Christopher L.ORCID, Shelat Anang A.ORCID, Baker Suzanne J.ORCID
Abstract
AbstractPediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. In vitro and in vivo disease models reflecting the intimate connection between developmental context and pathogenesis of pHGG are essential to advance understanding and identify therapeutic vulnerabilities. Here we report establishment of 21 patient-derived pHGG orthotopic xenograft (PDOX) models and eight matched cell lines from diverse groups of pHGG. These models recapitulate histopathology, DNA methylation signatures, mutations and gene expression patterns of the patient tumors from which they were derived, and include rare subgroups not well-represented by existing models. We deploy 16 new and existing cell lines for high-throughput screening (HTS). In vitro HTS results predict variable in vivo response to PI3K/mTOR and MEK pathway inhibitors. These unique new models and an online interactive data portal for exploration of associated detailed molecular characterization and HTS chemical sensitivity data provide a rich resource for pediatric brain tumor research.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute American Lebanese Syrian Associated Charities National Brain Tumor Society
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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