Longitudinal single-cell multiomic atlas of high-risk neuroblastoma reveals chemotherapy-induced tumor microenvironment rewiring
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.
Authors
- Kai Tan (ORCID: https://orcid.org/0000-0002-9104-5567)
- Peng Gao (ORCID: https://orcid.org/0000-0003-2341-1091)
- John M. Maris (ORCID: https://orcid.org/0000-0002-8088-7929)
- Rumeysa Biyik‐Sit
- Aliza Yousey
- Nancy R. Zhang (ORCID: https://orcid.org/0000-0002-0880-5749)
- Wenbao Yu (ORCID: https://orcid.org/0000-0001-8860-2644)
- Lea F. Surrey (ORCID: https://orcid.org/0000-0002-6944-2232)
- Daniel Martínez (ORCID: https://orcid.org/0000-0002-4723-9989)
- Anusha Thadi (ORCID: https://orcid.org/0000-0002-1271-0398)
- Michael D. Hogarty (ORCID: https://orcid.org/0000-0002-9221-4852)
- Changya Chen (ORCID: https://orcid.org/0000-0003-4421-2462)
- Liron D. Grossmann (ORCID: https://orcid.org/0000-0002-0692-8921)
- David Wei Wu (ORCID: https://orcid.org/0000-0001-6197-7091)
- Christina S. Turn (ORCID: https://orcid.org/0000-0003-3962-6740)
- Minxing Pang (ORCID: https://orcid.org/0000-0001-5208-5972)
- Shovik Bandyopadhyay (ORCID: https://orcid.org/0000-0003-3919-3914)
- Tasleema Patel (ORCID: https://orcid.org/0000-0002-7927-6071)
- Yasin Uzun (ORCID: https://orcid.org/0000-0002-6423-6085)
- Jeffrey Huang (ORCID: https://orcid.org/0000-0001-5574-6756)
- Kathrin M. Bernt (ORCID: https://orcid.org/0000-0002-0691-356X)
- Chia-Hui Chen (ORCID: https://orcid.org/0000-0001-5239-1574)
- Chi-Yun Wu (ORCID: https://orcid.org/0000-0003-4956-4133)
- Zhan Zhang (ORCID: https://orcid.org/0000-0002-9685-5753)
- Mei Zhang (ORCID: https://orcid.org/0000-0002-1543-4253)
- Jonathan Sussman (ORCID: https://orcid.org/0000-0002-3057-3550)
Institutions
- Pennsylvania State University (US)
- Children's Hospital of Philadelphia (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Sheba Medical Center (IL)
- First Affiliated Hospital of Xi'an Jiaotong University (CN)
- Applied Mathematics (United States) (US)
- Edmond and Lily Safra Children's Hospital (IL)
- Institute of Hematology & Blood Diseases Hospital (CN)
- University of Pennsylvania (US)
Publication Details
- Journal
- Nature Genetics
- Published
- 2025-04-14
- DOI
- https://doi.org/10.1038/s41588-025-02158-6
- Citations
- 19
- Primary Topic
- Neuroblastoma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 26.40
Funders
- American Cancer Society
- National Heart, Lung, and Blood Institute
- National Cancer Institute