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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月3日

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  • 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,
  • Zong-Ren Wang

摘要

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.