Single-cell transcriptomics identifies FOSL1-regulated IGFBP3+ melanoma subtype as a neuro-immunoregulatory signaling hub facilitating tumor progression

作者：Wenjia Ge, Ziwei Zhang, Wen-Jie Chen, Zhijie Zhao, Huabao Cai, Yantao Ding, Jin Xu · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1662869 · 被引用次数：1 · 研究领域：Cancer Immunotherapy and Biomarkers、Ferroptosis and cancer prognosis、Melanoma and MAPK Pathways

Background The most aggressive type of skin cancer, melanoma, has a high prevalence of metastases and a poor prognosis. Despite advancements in treatment, drug resistance and tumor microenvironment heterogeneity, especially involving neuro-immune interactions, continue to exist. The goal of this study is to uncover the cellular heterogeneity of melanoma in order to pinpoint molecular targets and tumor-promoting subtypes. Methods Melanoma single-cell RNA sequencing data came from GEO. Twelve cell types were discovered after Harmony batch effect adjustment and Seurat quality control; melanoma cells were subtyped. Functional expression of differential genes was examined using gene ontology and gene set enrichment. Cytotrace measured subtype differentiation potency. PySCENIC revealed transcription factor regulatory networks, and CellChat predicted intercellular communication between malignant cell subtypes and other cell types. Functional experiments with A375 and MEWo cell lines—lentiviral shRNA knockdown, CCK-8 proliferation, wound healing, transwell migration, and flow cytometry apoptotic assays—confirmed the analysis. Results Single-cell RNA sequencing was utilized to analyze melanoma cell subtypes and their interactions in the tumor microenvironment. C2 IGFBP3 +, which had the lowest CytoTRACE2 score and was enriched in late tumor stages, affected melanoma development. This subtype expressed prominent immunomodulatory pathways. The C2 subtype mediate signaling to fibroblasts...