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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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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| author | 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 |
| author_facet | 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 |
| author_sort | Wei Ou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9124bc2c6ea9414b8e44768053734a0c |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9124bc2c6ea9414b8e44768053734a0c2025-08-20T03:07:43ZengNature PortfolioNature Communications2041-17232025-04-0116111710.1038/s41467-025-58569-wIntegrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype-specific therapeutic strategiesWei Ou0Xin-Xin Zhang1Bin Li2Ying Tuo3Ren-Xuan Lin4Peng-Fei Liu5Jian-Ping Guo6Hio-Cheng Un7Ming-Hao Li8Jia-Hao Lei9Xiao-Jing Gao10Fu-Fu Zheng11Ling-Wu Chen12Ling-Li Long13Zong-Ren Wang14Department of Urology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Urology, The First Affiliated Hospital, Sun Yat-sen UniversityClinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Pathology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Urology, The First Affiliated Hospital, Sun Yat-sen UniversityShanghai Applied Protein Technology Co., LtdInstitute of Precision Medicine, the First Affiliated Hospital, Sun Yat-sen University, GuangzhouDepartment of Urology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Urology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Urology, The First Affiliated Hospital, Sun Yat-sen UniversityShanghai Applied Protein Technology Co., LtdDepartment of Urology, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Urology, The First Affiliated Hospital, Sun Yat-sen UniversityClinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen UniversityDepartment of Urology, The First Affiliated Hospital, Sun Yat-sen UniversityAbstract 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.https://doi.org/10.1038/s41467-025-58569-w |
| spellingShingle | 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 Integrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype-specific therapeutic strategies Nature Communications |
| title | Integrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype-specific therapeutic strategies |
| title_full | Integrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype-specific therapeutic strategies |
| title_fullStr | Integrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype-specific therapeutic strategies |
| title_full_unstemmed | Integrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype-specific therapeutic strategies |
| title_short | Integrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype-specific therapeutic strategies |
| title_sort | integrated proteogenomic characterization of localized prostate cancer identifies biological insights and subtype specific therapeutic strategies |
| url | https://doi.org/10.1038/s41467-025-58569-w |
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