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Dryad

Single-cell and spatial RNA sequencing identify divergent microenvironments and progression signatures in early- versus late-onset prostate cancer

Abstract

The clinical and pathological outcomes differ between early- (EOPC; diagnosed in men ≤ 55 years of age) and late-onset prostate cancer (LOPC), potentially attributed to the changes in hormone levels and immune activities associated with ageing. Exploring the heterogeneity therein holds the potential for developing age-specific precision interventions. Here, through single-cell and spatial transcriptomic analyses of prostate cancer tissues, we identified that an androgen response-related transcriptional meta-program (AR-MP) might underlie the age-related heterogeneity of tumour cells and microenvironment. APOE+ tumour-associated macrophages infiltrated AR-MP-activated tumour cells in EOPC, potentially facilitating tumour progression and immunosuppression. By contrast, inflammatory cancer-associated fibroblasts in LOPC could downregulate the AR-MP of tumour cells, promote epithelial-to-mesenchymal transition and induce pre-existing castration resistance, which effects could also be caused by smoking. This study provides insight into precision treatments tailored to diverse age groups, emphasizing interventions that include targeting AR and tumour-associated macrophages in young patients but anchoring epithelial-to-mesenchymal transition and inflammatory cancer-associated fibroblasts in old counterparts.