Early dissemination is a unique characteristic and a detrimental process of pancreatic ductal adenocarcinoma (PDAC); however, the underlying mechanism remains largely unknown. Here, we investigate the role of dual-specificity phosphatase-2 (DUSP2)-vascular endothelial growth factor-C (VEGF-C) axis in mediating PDAC lymphangiogenesis and lymphovascular invasion. Expression of DUSP2 is greatly suppressed in PDAC, which results in increased aberrant expression of extracellular vesicle (EV)-associated VEGF-C secretion. EV-VEGF-C exerts paracrine effects on lymphatic endothelial cells and autocrine effects on cancer cells, resulting in the lymphovascular invasion of cancer cells. Tissue-specific knockout of Dusp2 in mouse pancreas recapitulates PDAC phenotype and lymphovascular invasion. Mechanistically, loss-of-DUSP2 enhances proprotein convertase activity and vesicle trafficking to promote the release of the mature form of EV-VEGF-C. Collectively, these findings represent a conceptual advance in understanding pancreatic cancer lymphovascular invasion and suggest that loss-of-DUSP2-mediated VEGF-C processing may play important roles in early dissemination of pancreatic cancer. Abbreviations: DUSP2: dual-specificity phosphatase-2; VEGF-C: vascular endothelial growth factor-C; EV: extracellular vesicles; PDAC: pancreatic ductal adenocarcinoma; KD: knockdown.

中文翻译：

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DUSP2调节细胞外小泡-VEGF-C的分泌和胰腺癌的早期传播。

早期传播是胰腺导管腺癌（PDAC）的独特特征和有害过程。但是，其基本机制仍然未知。在这里，我们调查双重特异性磷酸酶2（DUSP2）-血管内皮生长因子-C（VEGF-C）轴在介导PDAC淋巴管生成和淋巴管浸润中的作用。DUSP2的表达在PDAC中被大大抑制，这导致与细胞外小泡（EV）相关的VEGF-C分泌异常表达增加。EV-VEGF-C对淋巴管内皮细胞发挥旁分泌作用，对癌细胞发挥自分泌作用，导致癌细胞淋巴血管浸润。小鼠胰腺中Dusp2的组织特异性敲除概括了PDAC表型和淋巴血管的侵袭。机械上，DUSP2缺失可增强前蛋白转化酶活性并促进小泡运输，从而促进EV-VEGF-C成熟形式的释放。总的来说，这些发现代表了在理解胰腺癌淋巴管浸润方面的概念性进展，并表明，DUSP2介导的VEGF-C加工缺失可能在胰腺癌的早期传播中起重要作用。缩写：DUSP2：双重特异性磷酸酶2；VEGF-C：血管内皮生长因子-C；EV：细胞外囊泡；PDAC：胰腺导管腺癌；KD：击倒。这些发现代表了在理解胰腺癌淋巴管浸润方面的概念性进展，并表明DUSP2介导的VEGF-C加工缺失可能在胰腺癌的早期传播中起重要作用。缩写：DUSP2：双重特异性磷酸酶2；VEGF-C：血管内皮生长因子-C；EV：细胞外囊泡；PDAC：胰腺导管腺癌；KD：击倒。这些发现代表了在理解胰腺癌淋巴管浸润方面的概念性进展，并表明DUSP2介导的VEGF-C加工缺失可能在胰腺癌的早期传播中起重要作用。缩写：DUSP2：双重特异性磷酸酶2；VEGF-C：血管内皮生长因子-C；EV：细胞外囊泡；PDAC：胰腺导管腺癌；KD：击倒。