DUSP2 regulates extracellular vesicle-VEGF-C secretion and pancreatic cancer early dissemination

• Published in: Journal of extracellular vesicles 2020-01, Vol.9 (1), p.1746529-n/a
• Main Authors: Wang, Chu-An, Chang, I-Heng, Hou, Pei-Chi, Tai, Yu-Jing, Li, Wan-Ning, Hsu, Pei-Ling, Wu, Shang-Rung, Chiu, Wen-Tai, Li, Chien-Feng, Shan, Yan-Shen, Tsai, Shaw-Jenq
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Autocrine signalling; Cell adhesion & migration; Cell culture; DUSP2; Endothelial cells; Extracellular vesicles; lymphovascular invasion; Metastasis; Pancreatic cancer; Paracrine signalling; PDAC; Phenotypes; Phosphatase; Proprotein convertases; Proteins; Secretion; Tumors; Vascular endothelial growth factor; VEGF-C
• ISSN: 2001-3078; 2001-3078
• DOI: 10.1080/20013078.2020.1746529

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