Longitudinal single-cell multiomic atlas of high-risk neuroblastoma reveals chemotherapy-induced tumor microenvironment rewiring
Wenbao Yu, Rumeysa Biyik‐Sit, Yasin Uzun, Chia-Hui Chen, Anusha Thadi, Jonathan Sussman, Minxing Pang, Chi-Yun Wu, Liron D. Grossmann, Peng Gao, David W. Wu, Aliza Yousey, Mei Zhang, Christina S. Turn, Zhan Zhang, Shovik Bandyopadhyay, Jeffrey Huang, Tasleema Patel, Changya Chen, Daniel Martínez, Lea F. Surrey, Michael D. Hogarty, Kathrin M. Bernt, Nancy R. Zhang, John M. Maris, Kai Tan
Abstract
High-risk neuroblastoma, a leading cause of pediatric cancer mortality, exhibits substantial intratumoral heterogeneity, contributing to therapeutic resistance. To understand tumor microenvironment evolution during therapy, we longitudinally profiled 22 patients with high-risk neuroblastoma before and after induction chemotherapy using single-nucleus RNA and ATAC sequencing and whole-genome sequencing. This revealed profound shifts in tumor and immune cell subpopulations after therapy and identified enhancer-driven transcriptional regulators of neuroblastoma neoplastic states. Poor outcome correlated with proliferative and metabolically active neoplastic states, whereas more differentiated neuronal-like states predicted better prognosis. Proportions of mesenchymal neoplastic cells increased after therapy and a high proportion correlated with a poorer chemotherapy response. Macrophages significantly expanded towards pro-angiogenic, immunosuppressive and metabolic phenotypes. We identified paracrine signaling networks and validated the HB-EGF-ERBB4 axis between macrophage and neoplastic subsets, which promoted tumor growth through the induction of ERK signaling. These findings collectively reveal intrinsic and extrinsic regulators of therapy response in high-risk neuroblastoma.