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

Abstract

Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by early dissemination and poor drug response. Loss-of-function of dual specificity phosphatase 2 (DUSP2), a critical regulator of MAPKs signaling, is highly associated with cancer malignancies. Therefore, it may provide new therapeutic strategy if the actions of DUSP2 can be restored. Methods The tumor suppressor role of DUSP2 was demonstrated via DUSP2 re-expression in the orthotopic mouse model of pancreatic cancer and knockout of Dusp2 in the pancreas by transgenic mouse model. Immunohistochemical staining and histology analysis was performed to evaluate tumor development and progression. Bioinformatic analysis was utilized to identify potential drug which mimics DUSP2 re-expression. Pancreatic cancer cell survival, migration ability, and the expression and function of extracellular vesicle (EV) associated vascular endothelial growth factor C (VEGF-C) was measured. The effect of the novel HDAC inhibitor on pancreatic cancer progression was evalulated by orthotopic mouse model. Results Forced expression of DUSP2 abrogated tumor formation and loss of Dusp2 facilitated Kras-driven PDAC formation. Increased HDAC1 expression was found in PDAC and inhibition of HDAC showed similar gene profile as Kras knockdown and DUSP2 re-expression. Treatment with B390 inhibited growth and migration abilities of PDAC cells, decreased EV-associated VEGF-C expression, and suppressed lymphatic endothelial cell proliferation. In vivo, B390 not only suppressed tumor growth by increasing tumor cell death, it also inhibited lymphangiogenesis and lymphovascular invasion. Conclusions Our data provide the proof-of-concept evidence to demonstrate the potential of using novel HDAC inhibitor in PDAC treatment which alleviates loss-of-DUSP2-mediated pathological processes.

Epigenetic reprogramming enhances the therapeutic efficacy of osteoblast‐derived extracellular vesicles to promote human bone marrow stem cell osteogenic differentiation

“…Wang et al. used of the HDACi B390 to induce apoptosis in pancreatic cancer cells and decreased vascular endothelial growth factor C expression in secreted EVs, inhibiting the nanoparticles role in cancer progression (Wang et al., 2020). Herein, we investigated the influence of epigenetic reprogramming through TSA induced hyperacetylation, on the osteoinductive potency of osteoblast‐derived EVs as a novel engineering approach.…”