Integrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype-specific therapeutic strategies

Wei Ou, Xin-Xin Zhang, Bin Li, Ying Tuo, Ren-Xuan Lin, Peng-Fei Liu, Jian-Ping Guo, Hio-Cheng Un, Ming-Hao Li, Jia-Hao Lei, Xiao-Jing Gao, Fu-Fu Zheng, Ling-Wu Chen (), Ling-Li Long () and Zong-Ren Wang ()
Additional contact information
Wei Ou: Sun Yat-sen University
Xin-Xin Zhang: Sun Yat-sen University
Bin Li: Sun Yat-sen University
Ying Tuo: Sun Yat-sen University
Ren-Xuan Lin: Sun Yat-sen University
Peng-Fei Liu: Ltd
Jian-Ping Guo: Guangzhou
Hio-Cheng Un: Sun Yat-sen University
Ming-Hao Li: Sun Yat-sen University
Jia-Hao Lei: Sun Yat-sen University
Xiao-Jing Gao: Ltd
Fu-Fu Zheng: Sun Yat-sen University
Ling-Wu Chen: Sun Yat-sen University
Ling-Li Long: Sun Yat-sen University
Zong-Ren Wang: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Localized prostate cancer (PCa) is highly variable in their response to therapies. Although a fraction of this heterogeneity can be explained by clinical factors or genomic and transcriptomic profiling, the proteomic-based profiling of aggressive PCa remains poorly understood. Here, we profiled the genome, transcriptome, proteome and phosphoproteome of 145 cases of localized PCa in Chinese patients. Proteome-based stratification of localized PCa revealed three subtypes with distinct molecular features: immune subgroup, arachidonic acid metabolic subgroup and sialic acid metabolic subgroup with highest biochemical recurrence (BCR) rates. Further, we nominated NANS protein, a key enzyme in sialic acid synthesis as a potential prognostic biomarker for aggressive PCa and validated in two independent cohorts. Finally, taking advantage of cell-derived orthotopic transplanted mouse models, single-cell RNA sequencing (scRNA-seq) and immunofluorescence analysis, we revealed that targeting NANS can reverse the immunosuppressive microenvironment through restricting the sialoglycan-sialic acid-recognizing immunoglobulin superfamily lectin (Siglec) axis, thereby inhibiting tumor growth of PCa. In sum, we integrate multi-omic data to refine molecular subtyping of localized PCa, and identify NANS as a potential prognostic biomarker and therapeutic option for aggressive PCa.

Date: 2025
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DOI: 10.1038/s41467-025-58569-w

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