SFRP2⁺ fibroblasts orchestrate post-chemotherapy remodeling and define a tumor-driven prognostic program, NBTRP, in adrenal neuroblastoma.
5 affiliations
- 1Department of Obstetrics and Gynecology, Department of Paediatrics, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
- 2School of Biomedical Science, Hunan University, Changsha, China.
- 3Department of Pediatric Hematology and Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
- 4Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou, China.
- 5Department of Pediatric Hematology and Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. [email protected].
Abstract
Neuroblastoma (NB) is a highly heterogeneous pediatric cancer in which chemotherapy resistance and poor prognosis are tightly linked to the tumor microenvironment (TME). Yet, how chemotherapy reshapes stromal components, particularly cancer-associated fibroblasts (CAFs), and the clinical implications of these alterations remain unclear. Here, by integrating single-cell, spatial, and bulk RNA-seq data from nine NB datasets, we systematically characterized chemotherapy-induced TME remodeling. Fibroblast subtypes were defined through clustering, stemness estimation, and functional enrichment analyses, revealing SFRP2⁺ inflammatory CAFs (iCAFs) as the dominant fibroblast population enriched after chemotherapy in adrenal NB TME. These SFRP2⁺ iCAFs exhibited high expression of SFRP2, FBLN1, and chemokines CXCL2 and CXCL3, and were found to promote angiogenesis by signaling to endothelial cells through the CCL2/CXCL2/3/8-ACKR1 axis. Building on the chemotherapy-associated gene expression changes in adrenal NB tumor cells, we developed a 6-gene prognostic model, termed NBTRP. The NBTRP robustly stratified patient survival across multiple cohorts and was associated with reduced cytotoxic T cell infiltration, increased tumor purity, and distinct drug sensitivity profiles. High NBTRP scores predicted enhanced sensitivity to chemotherapeutic agents such as vinblastine and etoposide, as well as improved response to anti-PD-L1 immunotherapy. Functional validation further identified SERPINF1, the top NBTRP feature, as a key effector that promoted NB cell invasion in vitro and modulated drug responses to vincristine, etoposide, cisplatin and cyclophosphamide. Together, our findings uncover SFRP2⁺ iCAFs as pivotal mediators of post-chemotherapy TME remodeling and establish NBTRP and SERPINF1 as clinically relevant biomarkers that bridge tumor-stroma dynamics with prognosis and therapeutic guidance in adrenal neuroblastoma.
Related
- A COJEC-chemotherapy resistant model of Th-ALK(F1174L)/MYCN neuroblastoma offers insights into tumour immune evasion and development of the bone marrow metastatic niche
- Mycobacterial Lipids Orchestrate Infection Stage-Specific Remodeling of the Host Actin Cytoskeleton
- Clinical prognostic risk model optimization based on vascular density in neuroblastoma
- 683 Single-cell RNA-seq analysis of 9464D-GD2 neuroblastoma reveals immune remodeling after anti-CD40 and epigenetic modifier inhibitor therapy
- Loss of BAX in a neuroblastoma patient reveals delayed apoptosis but sustained chemotherapy sensitivity
BibTeX
@article{wu2026sfrp2,
title = {{SFRP2⁺ fibroblasts orchestrate post-chemotherapy remodeling and define a tumor-driven prognostic program, NBTRP, in adrenal neuroblastoma.}},
author = {Jun Wu and Jian Gu and Guodong Li and Ye Xu and Weihua Li and Yuanxing Liao and Chi Li and Wei Zhang and Dao Wang and Lichun Xie},
journal = {Cell death \& disease},
year = {2026},
month = aug,
doi = {10.1038/s41419-026-09132-y},
url = {https://europepmc.org/article/MED/42957633},
note = {CC BY},
}
RIS
TY - JOUR
TI - SFRP2⁺ fibroblasts orchestrate post-chemotherapy remodeling and define a tumor-driven prognostic program, NBTRP, in adrenal neuroblastoma.
AU - Jun Wu
AU - Jian Gu
AU - Guodong Li
AU - Ye Xu
AU - Weihua Li
AU - Yuanxing Liao
AU - Chi Li
AU - Wei Zhang
AU - Dao Wang
AU - Lichun Xie
PY - 2026
DA - 2026/08/01
JO - Cell death & disease
DO - 10.1038/s41419-026-09132-y
UR - https://europepmc.org/article/MED/42957633
AB - Neuroblastoma (NB) is a highly heterogeneous pediatric cancer in which chemotherapy resistance and poor prognosis are tightly linked to the tumor microenvironment (TME). Yet, how chemotherapy reshapes stromal components, particularly cancer-associated fibroblasts (CAFs), and the clinical implications of these alterations remain unclear. Here, by integrating single-cell, spatial, and bulk RNA-seq data from nine NB datasets, we systematically characterized chemotherapy-induced TME remodeling. Fibroblast subtypes were defined through clustering, stemness estimation, and functional enrichment analyses, revealing SFRP2⁺ inflammatory CAFs (iCAFs) as the dominant fibroblast population enriched after chemotherapy in adrenal NB TME. These SFRP2⁺ iCAFs exhibited high expression of SFRP2, FBLN1, and chemokines CXCL2 and CXCL3, and were found to promote angiogenesis by signaling to endothelial cells through the CCL2/CXCL2/3/8-ACKR1 axis. Building on the chemotherapy-associated gene expression changes in adrenal NB tumor cells, we developed a 6-gene prognostic model, termed NBTRP. The NBTRP robustly stratified patient survival across multiple cohorts and was associated with reduced cytotoxic T cell infiltration, increased tumor purity, and distinct drug sensitivity profiles. High NBTRP scores predicted enhanced sensitivity to chemotherapeutic agents such as vinblastine and etoposide, as well as improved response to anti-PD-L1 immunotherapy. Functional validation further identified SERPINF1, the top NBTRP feature, as a key effector that promoted NB cell invasion in vitro and modulated drug responses to vincristine, etoposide, cisplatin and cyclophosphamide. Together, our findings uncover SFRP2⁺ iCAFs as pivotal mediators of post-chemotherapy TME remodeling and establish NBTRP and SERPINF1 as clinically relevant biomarkers that bridge tumor-stroma dynamics with prognosis and therapeutic guidance in adrenal neuroblastoma.
SN - 2041-4889
ER -