Single-Cell-Informed Characterization of A Candidate S100A9-Associated Epithelial Program and Prognostic Signature in Bladder Cancer.

Abstract

Background: Bladder cancer exhibits substantial molecular heterogeneity, and adverse epithelial programs remain incompletely characterized at single-cell resolution. This study aimed to identify candidate epithelial programs and derive genes supporting prognostic modeling.

Methods: Single-cell RNA sequencing data were analyzed to annotate epithelial subtypes and infer malignant populations. Bulk transcriptomic cohorts were used for Cox regression, risk-model construction, pathway analysis, immune characterization, and cell-cell communication inference. Stearoyl-CoA desaturase (SCD) was experimentally assessed in bladder cancer cells.

Results: We identified 14 epithelial subtypes with cell-level differences across pathological T stages. C05 Epithelial-S100A9 showed basal-like features, proliferative signaling, and adverse program-level survival associations. GSE130001 showed broad C05-signature activity but no discrete C05-like subpopulation. From this program, we derived a four-gene signature comprising epoxide EPHX1, SCD, LDLR, and TSPAN8. High-risk tumors were enriched for epithelial-mesenchymal transition, collagen-associated pathways, immune-checkpoint expression, and fibroblast-related signaling. SCD knockdown reduced proliferation and migration.

Conclusions: This study characterizes a candidate S100A9-associated epithelial program and a single-cell-informed prognostic framework linked to stromal and immune features. These findings suggest potential prognostic relevance, but independent single-cell analyses, mechanistic studies, and prospective validation remain required.