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

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.