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DOCK3 在前列腺癌中调控转移和免疫微环境

英文原题：DOCK3 orchestrates metastasis and immune microenvironment in prostate cancer.

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DOCK3 orchestrates metastasis and immune microenvironment in prostate cancer.

PubMed 2025/10/22（内容时间） Front Urol Q3 · IF 1.7（JCR 2025）

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技术：NK 细胞前列腺癌地区：中国
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研究概要

DOCK3 通过细胞骨架动力学驱动 PCa 转移，同时矛盾性地促进免疫活跃的微环境。其肿瘤特异性表达及与侵袭性临床特征的关联，使 DOCK3 成为风险分层的新型生物标志物，以及免疫“冷”PCa 联合免疫治疗的有前景的治疗靶点。

研究思路结论见上方概要

背景

前列腺癌（PCa）是男性癌症死亡的主要原因，转移和免疫逃逸构成重大治疗挑战。DOCK3是一种参与细胞骨架动力学的鸟嘌呤核苷酸交换因子，在前列腺癌中研究甚少。本研究探讨DOCK3在前列腺癌转移和肿瘤免疫微环境（TIME）重塑中的作用。

方法

多组学分析整合了来自 TCGA-PRAD 的 bulk RNA-seq（499 例肿瘤/52 例正常）、来自 GEO 的 scRNA-seq（45,325 个细胞）以及基因组数据。我们进行了：差异表达分析（DESeq2）、免疫解卷积（CIBERSORT、ssGSEA、xCell）、WGCNA 共表达网络、肿瘤突变负荷（TMB）评估、远处转移（M1 vs. M0）关联研究、scRNA-seq 聚类（Harmony/UMAP）和 DE 检验。统计显著性阈值：|log2FC|>1，padj<0.05。

结果

发现DOCK3表达在转移性（M1）肿瘤中较原发性（M0）肿瘤显著升高（p<0.05），并且在转移性样本中与更高的肿瘤突变负荷（TMB）呈强正相关（p<0.001）。细胞特异性分析显示，DOCK3仅在恶性上皮细胞和基质细胞中独家且高度富集，特别是在Cluster 6中，其log2 fold-change为9.13（padj<1e-200），并在54%的细胞中表达，而在所有其他cluster中几乎不存在。在肿瘤微环境中，DOCK3表达升高与细胞毒性免疫浸润显著增加相关，尤其是CD8 + T细胞和Natural Killer细胞，这一发现得到多种计算算法的一致支持（均p<0.05）。在临床上，DOCK3高水平与转移状态显著相关（p<0.01），而CDKN3高表达则与晚期疾病特征相关，包括更高的Gleason评分（3-5）和T-stage（T2-T4）（p<0.01）。此外，在cluster之间观察到免疫浸润模式存在显著差异。通过WGCNA Green Module鉴定的与DOCK3共表达基因的通路富集分析表明，其显著参与细胞骨架重组、肌肉收缩和代谢通路等生物学过程（FDR<0.01）。

展开英文摘要原文
METHODS

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.

RESULTS

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).

CONCLUSION

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.

论文信息

作者
Han J、Zhang M、Zhou H、Xiong Q、Zhong X、Tan P
单位
Department of Urology, West China Hospital of Sichuan University, Chengdu,&#xa0;China.China
期刊
Frontiers in urology2025
原文标识
PubMed 41200217　·　DOI 10.3389/fruro.2025.1662692

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