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<p>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.</p>

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Longitudinal single-cell multiomic atlas of high-risk neuroblastoma reveals chemotherapy-induced tumor microenvironment rewiring

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月14日

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  • Wenbao Yu,
  • Rumeysa Biyik-Sit,
  • Yasin Uzun,
  • Chia-Hui Chen,
  • Anusha Thadi,
  • Jonathan H. 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 Martinez,
  • Lea F. Surrey,
  • Michael D. Hogarty,
  • Kathrin Bernt,
  • Nancy R. Zhang,
  • John M. Maris,
  • Kai Tan

摘要

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.