{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T23:50:24Z","timestamp":1787701824785,"version":"build-2784847793"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Urol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Prostate cancer (PCa) is a leading cause of male cancer mortality, with metastasis and immune evasion posing major therapeutic challenges. DOCK3, a guanine nucleotide exchange factor implicated in cytoskeletal dynamics, is poorly characterized in PCa. This study investigates DOCK3\u2019s role in PCa metastasis and tumor immune microenvironment (TIME) remodeling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Multi-omics analyses integrated bulk RNA-seq from TCGA-PRAD (499 tumors\/52 normals), scRNA-seq from GEO (45,325 cells), and genomic data. We performed: Differential expression analysis (DESeq2), Immune deconvolution (CIBERSORT,ssGSEA, xCell), WGCNA co-expression networks, Tumor mutational burden (TMB) assessment, Distant metastasis (M1 vs. M0) association studies, scRNA-seq clustering (Harmony\/UMAP) and DE testing. Statistical significance thresholds: |log2FC|&amp;gt;1, padj&amp;lt;0.05.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      DOCK3 expression was found to be significantly elevated in metastatic (M1) tumors compared to primary (M0) tumors (p&amp;lt;0.05) and demonstrated a strong positive correlation with a higher tumor mutational burden (TMB) in metastatic samples (p&amp;lt;0.001). Cellular specificity analysis revealed that DOCK3 was exclusively and highly enriched within malignant epithelial and stromal cells, specifically in Cluster 6, where it exhibited a log2 fold-change of 9.13 (padj&amp;lt;1e-200) and was expressed in 54% of cells, compared to a negligible presence in all other clusters. In the tumor microenvironment, elevated DOCK3 expression was associated with a significant increase in cytotoxic immune infiltration, notably of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T and Natural Killer cells, a finding consistently supported by multiple computational algorithms (all p&amp;lt;0.05). Clinically, a high level of DOCK3 was significantly associated with metastatic status (p&amp;lt;0.01), whereas high expression of CDKN3 was correlated with advanced disease features, including higher Gleason scores (3-5) and T-stage (T2-T4) (p&amp;lt;0.01). Furthermore, significant differences in immune infiltration patterns were observed between clusters. Pathway enrichment analysis of genes co-expressed with DOCK3, identified through the WGCNA Green Module, indicated significant involvement in biological processes such as cytoskeletal reorganization, muscle contraction, and metabolic pathways (FDR&amp;lt;0.01).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>DOCK3 drives PCa metastasis through cytoskeletal dynamics while paradoxically promoting an immunologically active microenvironment. Its tumor-specific expression and association with aggressive clinical features nominate DOCK3 as a novel biomarker for risk stratification and a promising therapeutic target for combinatorial immunotherapy in immunologically \u201ccold\u201d PCa.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fruro.2025.1662692","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T05:32:49Z","timestamp":1761111169000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["DOCK3 orchestrates metastasis and immune microenvironment in prostate 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