DOCK3 orchestrates metastasis and immune microenvironment in prostate cancer

TL;DR

DOCK3 is linked to prostate cancer metastasis and immune response, suggesting it could be a new target for treatment.

Contribution

DOCK3 is newly identified as a driver of metastasis and immune microenvironment remodeling in prostate cancer.

Findings

DOCK3 is significantly elevated in metastatic prostate tumors and correlates with higher tumor mutational burden.

DOCK3 expression is enriched in malignant epithelial and stromal cells and is associated with increased cytotoxic immune infiltration.

DOCK3 is linked to aggressive clinical features and may serve as a biomarker for risk stratification and immunotherapy.

Abstract

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’s role in PCa metastasis and tumor immune microenvironment (TIME) remodeling.

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|>1, padj<0.05.

DOCK3 expression was found to be significantly elevated in metastatic (M1) tumors compared to primary (M0) tumors (p<0.05) and demonstrated a strong positive correlation with a higher tumor mutational burden (TMB) in metastatic samples (p<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<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+ T and Natural Killer cells, a finding consistently supported by multiple computational algorithms (all p<0.05). Clinically, a high level of DOCK3 was significantly associated with metastatic status (p<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<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<0.01).

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 “cold” PCa.

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