Patient-derived models recapitulate heterogeneity of molecular signatures and drug response in pediatric high-grade glioma
| Autor: | Amar Gajjar, Jinghui Zhang, Yingzhe Wang, Xiaoyan Zhu, William Caufield, Chen He, Xiaoyu Li, Burgess B. Freeman, Zoran Rankovic, Gang Wu, Michelle Monje, Nathaniel R. Twarog, Duane G. Currier, Taosheng Chen, Kimberly S Mercer, Barbara Jonchere, Jason Chiang, Ke Xu, Lawryn H. Kasper, Jia Xie, Laura D. Hover, Ibrahim Qaddoumi, Christopher L. Tinkle, Cynthia Wetmore, Wenwei Lin, Anang A. Shelat, Paul Klimo, Giles W. Robinson, Santhosh A. Upadhyaya, Suzanne J. Baker, Brent A. Orr, Alberto Broniscer, Frederick A. Boop, Paige S. Dunphy, Martine F. Roussel, Paul A. Northcott, Brian Gudenas, Chang-Hyuk Kwon, James T. Dalton, Junyuan Zhang |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Science General Physics and Astronomy Context (language use) Disease General Biochemistry Genetics and Molecular Biology Article Paediatric cancer 03 medical and health sciences Genetic Heterogeneity Mice 0302 clinical medicine In vivo Glioma Cell Line Tumor medicine Animals Humans Cancer models Child Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Cancer Cell Proliferation Regulation of gene expression Multidisciplinary business.industry Brain Neoplasms TOR Serine-Threonine Kinases General Chemistry medicine.disease Xenograft Model Antitumor Assays High-Throughput Screening Assays CNS cancer Gene Expression Regulation Neoplastic Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis DNA methylation Mutation Cancer research business |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-17 (2021) |
| ISSN: | 2041-1723 |
| Popis: | 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. Patient-derived xenografts provide a resource for basic and translational cancer research. Here, the authors generate multiple pediatric high-grade glioma xenografts, use omics technologies to show that they are representative of primary tumours and use them to assess therapeutic response. |
| Databáze: | OpenAIRE |
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