Journal Article

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

Mercer, Kimberly S., Dunphy, Paige S., Twarog, Nathaniel, Currier, Duane G., Kwon, Chang-Hyuk, Gudenas, Brian, Xie, Jia, Upadhyaya, Santhosh A., Zhang, Jinghui, Northcott, Paul A., Shelat, Anang A., Zhang, Junyuan, Chen, Taosheng, Rankovic, Zoran, Chiang, Jason, Kasper, Lawryn H., Orr, Brent A., Li, Xiaoyu, Dalton, James, Wetmore, Cynthia, Hover, Laura D., Wu, Gang, He, Chen, Lin, Wenwei, Xu, Ke, Baker, Suzanne J., Jonchere, Barbara, Qaddoumi, Ibrahim, Gajjar, Amar, Roussel, Martine F., Boop, Frederick, Broniscer, Alberto, Wang, Yingzhe, Robinson, Giles W., Monje, Michelle, Klimo, Paul, Caufield, William, Freeman III, Burgess B., Zhu, Xiaoyan, Tinkle, Christopher L.

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 1-Phosphatidylinositol 3-kinase / 13 / 13/106 / 38 / 38/39 / 45 / 49/47 / 631/67 / 631/67/1922 / 631/67/2332 / 631/67/70 / 64 / 64/60 / 96 / Brain cancer / Brain tumors / Cancer / Cancer research / Cell culture / Deoxyribonucleic acid / DNA / DNA methylation / Gene expression / Glioma / Heterogeneity / High-throughput screening / Histopathology / Human health and pathology / Humanities and Social Sciences / Life Sciences / Medical research / Molecular modelling / multidisciplinary / Mutation / Pathogenesis / Pediatrics / Science / Science (multidisciplinary) / Signatures / Subgroups / TOR protein / Tumors / Xenografts / Xenotransplantation