Prostate cancer is the most 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 would provide insight to improve patient stratification and develop efficient treatment strategies.
In a study published in Nature Communications, presents collaborative work by multiple research teams, including 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, QIU Xuefeng's team from Nanjing University Affiliated Drum Tower Hospital, TANG Huiru's group from Fudan University, CHEN Luonan's team from Shanghai Jiao Tong University, and HUANG Shengsong's team from Tongji Hospital Affiliated with Tongji University, entitled “Analysis of the transcriptomic and metabolomic landscape of prostate cancer with different anatomical origins using snFLARE-seq and mxFRIZNGRND” . This research characterizes the molecular features of prostate cancers from distinct anatomical origins and delineates their dynamic evolution following hormone therapy, providing new scientific insights for developing clinical intervention strategies.
The research team retrospectively 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 disease characteristics of prostate cancers from different zonal origins, the team developed the snFLARE-seq and mxFRIZNGRND methodologies for FFPE samples.
Using these technologies, the team 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 study revealed that hormone therapy can induce epithelial cells to transition into more aggressive subtypes, reinforcing and polarizing the features of peripheral zone-type prostate cancer. Concurrently, it drastically alters the immune microenvironment, leading to a significantly immunosuppressive state. Cell communication analysis indicated that the interactions between cancer cells and the microenvironment are 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 research team 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.
Reference：https://www.nature.com/articles/s41467-026-69347-7
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