Open AccessDUSP2 regulates extracellular vesicle‐VEGF‐C secretion and pancreatic cancer early dissemination
Author(s) -
Wang ChuAn,
Chang IHeng,
Hou PeiChi,
Tai YuJing,
Li WanNing,
Hsu PeiLing,
Wu ShangRung,
Chiu WenTai,
Li ChienFeng,
Shan YanShen,
Tsai ShawJenq
Publication year - 2020
Publication title -
journal of extracellular vesicles
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.94
H-Index - 68
ISSN - 2001-3078
DOI - 10.1080/20013078.2020.1746529
Subject(s) - autocrine signalling , lymphangiogenesis , pancreatic cancer , lymphovascular invasion , paracrine signalling , cancer research , vascular endothelial growth factor , medicine , cancer , vegf receptors , metastasis , receptor
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