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

作者：Wei Ou, Xin-Xin Zhang, Bin Li, Ying Tuo, Renxuan Lin, Pengfei Liu, Jianping Guo, Hiocheng Un, Minghao Li, Jiahao Lei, Xiaojing Gao, Fufu Zheng, Lingwu Chen, Lingli Long, Zongren Wang · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-58569-w · 被引用次数：13 · 研究领域：Cancer-related molecular mechanisms research、Immunotherapy and Immune Responses、Prostate Cancer Treatment and Research

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.