Abstract Prostate cancer cells of different anatomical locations display remarkable heterogeneity. This poses a challenge to the clinical relevance of pre-clinical models and the efficacy of contemporary therapeutic approaches. Here we develop the snFLARE-seq and mxFRIZNGRND methodologies to directly investigate the transcriptomic and metabolomic landscape of prostate cancer patients utilizing formalin-fixed paraffin-embedded (FFPE) specimens. A retrospective analysis reveals the clinical disparities of prostate cancer from peripheral zone (PZ), transition zone (TZ), and across PZ and TZ. The snFLARE-seq, refined for enhanced single-nucleus sequencing, unveils distinct cell type distributions and signaling pathways between PZ and TZ samples. Hormone therapy substantially affects cancer cells and microenvironment, leading to a polarized feature of epithelial cells and a subverted immune microenvironment. With improvements in metabolite extraction, mxFRIZNGRND reveals unique metabolic features of prostate cancer from different origins. The metabolomic results indicate that PZ cancer cells are in a metabolic-dormant status, which are probably awaken by hormone therapy. Integrative analysis of results from snFLARE-seq, mxFRIZNGRND, and TCGA database uncovers four metabolic pathways and related genes associated with disease aggressiveness. Our work could accelerate investigations on disease heterogeneity and evolution in real-world clinical settings, stimulating patient-specific precision healthcare solutions.
He et al. (2026) studied this question.