Jonathan Sussman, Derek A. Oldridge, Wenbao Yu, Chia‐Hui Chen, Abigail M. Zellmer, Jiazhen Rong, Arianne Parvaresh-Rizi, Anusha Thadi, Austin Yang, Joseph S. Tumulty, Barbara Xiong, David Wu, Yusha Sun, Shovik Bandyopadhyay, Jason Xu, Stephanie Brosius, Una Yamamoto Barkardottir, Isabelle Seka, Kyung Jin Ahn, Omar Elghawy, Amy E. Baxter, Mateusz Koptyra, R. Vanguri, Stephanie McGrory, Phillip B. Storm, Nduka Amankulor, Mariarita Santi, Angela N. Viaene, Nancy R. Zhang, Thomas De Raedt, Kristina A. Cole, Kai Tan
Pediatric high-grade glioma (pHGG) is an incurable central nervous system malignancy that is a leading cause of pediatric cancer death. While pHGG shares many similarities with adult glioma, it comprises distinct disease entities. In this study, we longitudinally profile a molecularly diverse cohort of 16 pHGG patients through single-nucleus RNA and ATAC sequencing, whole-genome sequencing, and CODEX spatial proteomics to capture the evolution of neoplastic and microenvironmental features during disease progression and treatment. We define a set of core pHGG neoplastic cell states and observe differential tumor-myeloid interactions between malignant cell phenotypes. We find that essential neuromodulators and the interferon response are upregulated post-therapy, implicating them as malignant cell-intrinsic targets. We observe an increase in oligodendrocytes upon progression and that they coordinate spatial motifs with proneural tumor cells. This multiomic atlas of longitudinal pHGG captures features of therapy response and provides a scalable reference for the study of pediatric brain tumors.