Multimodal integration of pathomics and single-cell transcriptomics reveals CDC20 as a link between prostate cancer recurrence and benzo[a]pyrene-responsive phenotypes.

INTRODUCTION: Prostate cancer recurrence reflects molecular and histological heterogeneity, yet the cellular states harboring recurrence-associated signals and their potential environmental modifiers remain incompletely understood. METHODS: We integrated single-cell RNA sequencing, bulk transcriptomes with recurrence annotation, quantitative histopathology, cross-cohort survival modeling, reverse network toxicology, molecular simulation, and cellular perturbation experiments. RESULTS: Analysis of 36,025 cells from GSE141445 identified 14,464 malignant luminal epithelial cells. Scissor identified a recurrence-associated transcriptional state enriched for adhesion, migration, angiogenesis, and proliferation programs. H&E-derived features from 304 paired TCGA-PRAD cases captured variation in this transcriptional program and supported internal recurrence risk stratification. Cross-cohort modeling prioritized CDC20, ENSA, and PTTG1. Reverse toxicology further prioritized benzo[a]pyrene (BaP), and CDC20 showed the most favorable predicted BaP docking score. In PC-3 and DU145 cells, 10 nM BaP increased CDC20 expression, whereas CDC20 silencing attenuated BaP-associated proliferation, colony formation, wound closure, and migration. DISCUSSION: These findings identify CDC20 as a recurrence-associated molecular node involved in BaP-responsive malignant biological phenotypes and provide a phenotype-anchored framework linking recurrence biology with environmental exposure-related tumor behavior.