Patient-derived xenografts of matched primary-recurrent pediatric brain tumors as a resource for identifying therapy resistance profiles

Abstract Tumor recurrence developing from therapy resistance, immune escape and metastasis is the leading cause of death of malignant pediatric brain tumors. By studying paired primary-recurrent patient samples we previously identified significant accumulation of SOX9-positive cells in Group 3 medulloblastoma that was similarly induced following long-term irradiation in transgenic mouse models of MYC-induced medulloblastoma. To follow relapse biology in malignant pediatric brain tumors at the single cell level we have established patient-derived xenografts (PDXs) from a number of matched primary-relapse samples, including pediatric high-grade glioma, medulloblastoma and ependymoma profiled with DNA methylation analysis. We next used scRNA-Seq to identify clones with particular expression of genes and distinct signaling pathways enriched in recurrent tumor cells as compared to their matched primary tumor cells. We further used a lentivirus-based barcoding strategy coupled to scRNA-Seq to study the molecular evolution of cell clones arising from genetically modified mouse models and PDXs that survive long-term fractionated irradiation, cisplatin or temozolomide treatment in vitro and in vivo. By using computational modeling we identified means of specific targeting of recurrent cells that could be of potential use in future treatments for patients affected by fatal relapses. Our results suggest that pediatric brain tumors of distinct tumor entities use different ways to acquire therapy resistance in patients which is often coupled to an expansion of clones that are developing therapy-induced resistance.