Integrative Multi-Omics and Single-Cell Analyses Identify FKBP10 as a CAF-Associated Biomarker Linked to ECM Remodeling and Aggressiveness in Neuroblastoma

Abstract

: Objectives: Neuroblastoma (NB) is a heterogeneous pediatric malignancy driven by both intrinsic oncogenic programs and the stromal microenvironment. However, the critical stromal regulators associated with poor prognosis and metastasis in NB remain poorly characterized. This study aimed to identify key cancer-associated fibroblast (CAF)-related genes and to investigate the clinical significance, biological function, and molecular mechanism of FKBP10 in NB malignant progression. Methods: Multi-cohort bioinformatic analyses, including weighted gene co-expression network analysis, machine learning-based LASSO-Cox modeling, and single-cell transcriptomics were performed to screen core stromal biomarkers. In vitro functional assays, rescue experiments, drug sensitivity assays, and in vivo xenograft models were used to validate the oncogenic role of FKBP10 in NB. Results: High CAF infiltration correlated with unfavorable prognosis in NB. FKBP10 was identified as a core stromal effector highly expressed in fibroblasts and malignant NB cells. The FKBP10 -based signature effectively stratified patient prognosis in primary and validation cohorts. Mechanistically, FKBP10 facilitated extracellular matrix (ECM) remodeling and mesenchymal reprogramming, accompanied by tumor immune evasion and therapeutic resistance. Functional assays demonstrated that FKBP10 depletion suppressed NB proliferation, migration, invasion, and tumor growth, while restoring FKBP10 rescued malignant phenotypes and reduced chemosensitivity. Conclusions: FKBP10 promotes aggressive NB progression by regulating stromal activation, ECM remodeling and malignant behaviors. FKBP10 serves as a reliable prognostic biomarker and a promising therapeutic target for high-risk neuroblastoma.