Patient-derived models recapitulate heterogeneity of molecular signatures and drug response in pediatric high-grade glioma

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, William; Wang, Yingzhe; Xie, Jia; Broniscer, Alberto; Wetmore, Cynthia; Upadhyaya, Santhosh A.; Qaddoumi, Ibrahim; Klimo, Paul; Boop, Frederick; Gajjar, Amar; Zhang, Jinghui; Orr, Brent A.; Robinson, Giles W.; Monje, Michelle; Freeman, Burgess B.; Roussel, Martine F.; Northcott, Paul A.; Chen, Taosheng; Rankovic, Zoran; Wu, Gang; Chiang, Jason; Tinkle, Christopher L.; Shelat, Anang A.; Baker, Suzanne J.

Patient-derived models recapitulate heterogeneity of molecular signatures and drug response in pediatric high-grade glioma

Chen He, Ke Xu, Xiaoyan Zhu, Paige S. Dunphy, Brian Gudenas, Wenwei Lin, Nathaniel Twarog, Laura D. Hover, Chang-Hyuk Kwon, Lawryn H. Kasper, Junyuan Zhang, Xiaoyu Li, James Dalton, Barbara Jonchere, Kimberly S. Mercer, Duane G. Currier, William Caufield, Yingzhe Wang, Jia Xie, Alberto Broniscer, Cynthia Wetmore, Santhosh A. Upadhyaya, Ibrahim Qaddoumi, Paul Klimo, Frederick Boop, Amar Gajjar, Jinghui Zhang, Brent A. Orr, Giles W. Robinson, Michelle Monje, Burgess B. Freeman, Martine F. Roussel, Paul A. Northcott, Taosheng Chen, Zoran Rankovic, Gang Wu, Jason Chiang (), Christopher L. Tinkle (), Anang A. Shelat () and Suzanne J. Baker ()
Additional contact information
Chen He: Department of Developmental Neurobiology
Ke Xu: Center for Applied Bioinformatics
Xiaoyan Zhu: Department of Developmental Neurobiology
Paige S. Dunphy: Department of Developmental Neurobiology
Brian Gudenas: Department of Developmental Neurobiology
Wenwei Lin: Department of Chemical Biology and Therapeutics
Nathaniel Twarog: Department of Chemical Biology and Therapeutics
Laura D. Hover: Department of Developmental Neurobiology
Chang-Hyuk Kwon: Department of Developmental Neurobiology
Lawryn H. Kasper: Department of Developmental Neurobiology
Junyuan Zhang: Department of Developmental Neurobiology
Xiaoyu Li: Department of Pathology
James Dalton: Department of Pathology
Barbara Jonchere: Department of Tumor Cell Biology
Kimberly S. Mercer: Department of Tumor Cell Biology
Duane G. Currier: Department of Chemical Biology and Therapeutics
William Caufield: Preclinical Pharmacokinetics Shared Resource St. Jude Children’s Research Hospital
Yingzhe Wang: Preclinical Pharmacokinetics Shared Resource St. Jude Children’s Research Hospital
Jia Xie: Department of Chemical Biology and Therapeutics
Alberto Broniscer: Children’s Hospital of Pittsburgh
Cynthia Wetmore: Exelixis, Inc.
Santhosh A. Upadhyaya: Department of Oncology
Ibrahim Qaddoumi: Department of Oncology
Paul Klimo: St. Jude Children’s Research Hospital
Frederick Boop: St. Jude Children’s Research Hospital
Amar Gajjar: Department of Oncology
Jinghui Zhang: Department of Computational Biology
Brent A. Orr: Department of Pathology
Giles W. Robinson: Department of Oncology
Michelle Monje: Stanford University
Burgess B. Freeman: Preclinical Pharmacokinetics Shared Resource St. Jude Children’s Research Hospital
Martine F. Roussel: Department of Tumor Cell Biology
Paul A. Northcott: Department of Developmental Neurobiology
Taosheng Chen: Department of Chemical Biology and Therapeutics
Zoran Rankovic: Department of Chemical Biology and Therapeutics
Gang Wu: Center for Applied Bioinformatics
Jason Chiang: Department of Pathology
Christopher L. Tinkle: St. Jude Children’s Research Hospital
Anang A. Shelat: Department of Chemical Biology and Therapeutics
Suzanne J. Baker: Department of Developmental Neurobiology

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Pediatric 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.

Date: 2021
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DOI: 10.1038/s41467-021-24168-8

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