Integrative analysis of single-cell and bulk RNA sequencing reveals inflammatory mechanisms of cancer-induced nerve injury and enables prognostic modeling in lung adenocarcinoma.
Abstract
Background
Cancer-induced nerve injury (CINI) is implicated in unfavorable clinical outcomes across multiple cancer types. However, its biological role and prognostic value remain insufficiently characterized in lung adenocarcinoma (LUAD).
Methods
Bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics datasets were integrated to investigate CINI-related molecular features in LUAD. Survival analysis was performed to evaluate the prognostic significance of CINI-related transcriptional activity. Immune infiltration analysis, functional enrichment analysis, and tumor microenvironment (TME) profiling were conducted to explore the association between CINI and immune environment. Weighted gene co-expression network analysis (WGCNA) and machine learning algorithms were further applied to construct a CINI-related prognostic signature. Single-cell and spatial transcriptomic analyses were used to identify CINI-associated epithelial cells, characterize their developmental states, and explore potential intercellular communication patterns. In vitro experiments were performed to validate the functional relevance of the selected risk gene.
Results
Survival analysis indicated a significant negative association between CINI activity and overall survival in LUAD patients across multiple transcriptomic cohorts. Single-cell and spatial transcriptomic analyses identified malignant transcriptional features, increased developmental plasticity, and preferential enrichment in metastatic lesions of CINI-associated epithelial cells. We further established a CINI-related prognostic model, and in vitro experiments supported the functional relevance of PLEK2 in LUAD cell proliferation and migration.
Conclusion
This study provided an integrative multi-omics characterization of CINI in LUAD and suggested that CINI activity was associated with TME remodeling and prognosis. These findings highlight the potential value of CINI-related signatures for prognostic stratification and future therapeutic exploration.