Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis.

Cancer Letters
Kosuke OgawaXiaoqun Dong

Abstract

To demonstrate multifaceted contribution of aspartate β-hydroxylase (ASPH) to pancreatic ductal adenocarcinoma (PDAC) pathogenesis, in vitro metastasis assay and patient derived xenograft (PDX) murine models were established. ASPH propagates aggressive phenotypes characterized by enhanced epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, extracellular matrix (ECM) degradation/remodeling, angiogenesis, stemness, transendothelial migration and metastatic colonization/outgrowth at distant sites. Mechanistically, ASPH activates Notch cascade through direct physical interactions with Notch1/JAGs and ADAMs. The ASPH-Notch axis enables prometastatic secretome trafficking via exosomes, subsequently initiates MMPs mediated ECM degradation/remodeling as an effector for invasiveness. Consequently, ASPH fosters primary tumor development and pulmonary metastasis in PDX models, which was blocked by a newly developed small molecule inhibitor (SMI) specifically against ASPH's β-hydroxylase activity. Clinically, ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stage PDAC. Relatively high levels of ASPH-Notch network components independently/jointly predict curtailed overall ...Continue Reading

Citations

Aug 20, 2020·Journal of Experimental & Clinical Cancer Research : CR·Madiha KanwalRuth Tachezy
Dec 29, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Yu-Shui MaDa Fu
Jan 21, 2021·Pharmaceutics·Adriana G Quiroz-ReyesElsa N Garza-Treviño
Nov 1, 2020·Drug Discovery Today·Batoul Farran, Ganji Purnachandra Nagaraju

❮ Previous
Next ❯

Related Concepts

Related Papers

Public Health Reports
Greg AlexanderAllison Foster
Public Health Reports
Public Health Reports
M A Potter, A Kindling
© 2021 Meta ULC. All rights reserved