Prostate cancer is one prevalent malignant tumor in men. Targeting androgen-androgen receptor (AR) axis is the mainstay for prostate cancer therapy. However, due to the intratumoral heterogeneity, treatment resistance is inevitable for some patients. Delineating the heterogeneity and evolutionary trajectories of prostate cancer will help to improve patient stratification and develop efficient treatment strategies.

In a study published in Nature Communications, LI Zhenfei's group from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, along with the collaborators, characterized the molecular features of prostate cancers from distinct anatomical origins and delineated their dynamic evolution following hormone therapy, providing new insights for developing clinical intervention strategies.

The researchers analyzed data from 488 patients who underwent radical prostatectomy. They found that prostate cancers originating from the peripheral zone (PZ) and those spanning multiple zones progressed more rapidly and were more prone to drug resistance. To investigate the characteristics of prostate cancers from different zonal origins, the researchers developed the snFLARE-seq and mxFRIZNGRND methodologies for formalin-fixed paraffin-embedded (FFPE) specimens.

Using these methodologies, the researchers performed multi-omics analysis on 14 prostate cancer foci, obtaining transcriptomic data from 101,729 cells and metabolomic data covering 1,773 metabolites. They systematically compared the molecular profiles of PZ-origin, transition zone (TZ)-origin, and post-neoadjuvant therapy residual cancers spanning multiple zones (PTM).

The results showed that hormone therapy could induce epithelial cells to transition into more aggressive subtypes, reinforcing and polarizing the features of peripheral zone-type prostate cancer, and it drastically altered the immune microenvironment, leading to a significantly immunosuppressive state. Cell communication analysis indicated that the interactions between cancer cells and the microenvironment were conserved across multiple cancer types, suggesting that such intercellular communication pathways may represent a promising direction for developing broad-spectrum anticancer strategies.

Metabolomic data further confirmed characteristic metabolic differences among prostate cancers of different zonal origins. By integrating metabolomic and single-nucleus transcriptomic data, the researchers identified key drivers of prostate cancer progression involving four major metabolic pathways and several critical genes, laying an important foundation for future exploration of novel therapeutic strategies.

This study could accelerate investigations on disease heterogeneity and evolution in real-world clinical settings, stimulating patient-specific precision healthcare solutions.