Analysis and functional validations of multiple cell death patterns for prognosis in prostate cancer.

Prostate cancer (PCa) has garnered significant attention due to its rising incidence, variable therapeutic outcomes, and the absence of reliable prognostic markers. The significance of different cell death patterns in tumor development underscores their potential as predictors of PCa prognosis. This study utilized The Cancer Genome Atlas (TCGA) datasets to evaluate the prognostic capabilities of 15 cell death patterns and established a Cell Death Index (CDI) signature based on necrosis and cuproptosis-related genes. The predictive efficacy of the CDI signature was validated in our PCa cohort and in two public datasets: Deutsches Krebsforschungszentrum (DKFZ) and Memorial Sloan-Kettering Cancer Center (MSKCC) PCa cohorts. Our comprehensive analysis examined the relationship between CDI signature and clinical characteristics, published prognostic signatures, gene mutations, immune cell infiltration, enrichment pathways, and drug sensitivity in PCa. In vitro and in vivo studies assessed the impact of EDA2R and LOXL2 on PCa progression. The CDI signature exhibited robust predictive performance across three independent validation sets, with 1-, 2-, 3-, 4-, and 5-year area under the curve (AUC) values in the TCGA cohort of 0.866, 0.77, 0.836, 0.776, and 0.787, respectively. Higher CDI scores were correlated with advanced T and N stages, elevated Gleason scores, increased immune cell infiltration, gene mutations, and drug sensitivity. EDA2R inhibited PCa cell proliferation and migration, related to tumor necrosis, while LOXL2 promoted these processes and was associated with cuproptosis. In summary, our study identified a novel CDI signature as an effective indicator for diagnosis, personalized treatment, and prognostic assessment in PCa.