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

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

doi:10.1038/s41467-021-24168-8

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.

Highlights

Pediatric high-grade glioma is a major contributor to cancer-related death in children
In addition to the eight cell lines established from these patient-derived orthotopic xenograft (PDOX) models, we evaluated methylation profiles from six previously reported diffuse intrinsic pontine gliomas (DIPG) cell lines[15] used in our preclinical testing experiments
To highlight the most selectively effective drug for each cell line, we calculated the area under the curve (AUC) from the DR of each drug and subtracted the median AUC for that drug calculated over all cell lines (Fig. 6a)

Summary

Introduction

Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. 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. 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. Different subclasses of pHGG are readily detected through comparisons of genome-wide DNA methylation profiles, which may reflect both the developmental origins of the tumors and the consequences of tumorigenic mutations[13] This epigenetic characterization allows a refined molecular classification of CNS tumors and is increasingly being incorporated into clinical practice. Detailed molecular characterization of these novel models and the results from HTS chemical sensitivity studies on the large cell line panel are available through an interactive online data portal providing a rich resource to the pediatric brain tumor research community

Methods

Results

Conclusion