Integrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype-specific therapeutic strategies
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 prof...
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| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-58569-w |
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| Summary: | 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. |
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| ISSN: | 2041-1723 |