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

Abstract

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.

A novel HDAC inhibitor suppresses extracellular vesicle VEGF-C-mediated lymphangiogenesis and pancreatic cancer early dissemination

“…Loss of DUSP2 expression correlates with cancer malignancies and constitutive ERK activation (6)(7)(8)19). Recently, we demonstrated that loss-of-DUSP2 promotes pancreatic cancer early dissemination, likely through lymphovasculature (9). In this study, we show that re-expression of DUSP2 is su cient to prevent tumor formation in the orthotopic mouse model of pancreatic cancer.…”

“…Conditional knockout of Dusp2 in the pancreas is referred to KDC mice (LSL-Kras G12D , Dusp2F/F, Pdx-1-Cre). CRISPR/Cas9 system was used for replacing endogenous mouse dusp2 as described (9). Mice were sacri ced at the age of 6 months and pancreases were harvested for IHC analysis.…”

“…It has been demonstrated that DUSP2 expression is suppressed by hypoxia and downregulation of DUSP2 promotes drug resistance and cancer stemness (6,8). In pancreatic cancer, loss of DUSP2 was observed at the early stage of pancreatic intraepithelial neoplasia (PanIN), and DUSP2 downregulation promotes LVI in the orthotopic mouse model (9). Considering the critical roles of DUSP2, identi cation of means to restore its function may be an alternative way to alleviate PDAC malignancy.…”

VEGFC negatively regulates the growth and aggressiveness of medulloblastoma cells

“…However, tumors are not homogeneous, and most authors describe the so-called “autocrine” effect of VEGFC as the effect generated locally, on a specific type of cells—especially tumor cells—bearing the receptors, by the VEGFC secreted by this very type of cells. Paracrine effect is described as an effect occurring when VEGFC is transported by vessels (lymphatics) towards more distant targets 54 – 56 . To ascertain the autocrine effect of VEGFC, internalization of tagged-VEGFC receptors might be implemented.…”

PLA2G16 is a mutant p53/KLF5 transcriptional target and promotes glycolysis of pancreatic cancer

“…PAAD cells secrete several types of cytokines and growth factors such as interleukin (IL)‐6, IL‐8, basic fibroblast growth factor, nerve growth factor and vascular endothelial growth factor. They are implicated in cell proliferation via paracrine or autocrine mechanisms 30‐32 . Therefore, endogenous LPAs and FFAs help transduct the signallings and accelerate cellular growth.…”