TY - JOUR
T1 - Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis
AU - Ogawa, Kosuke
AU - Lin, Qiushi
AU - Li, Le
AU - Bai, Xuewei
AU - Chen, Xuesong
AU - Chen, Hua
AU - Kong, Rui
AU - Wang, Yongwei
AU - Zhu, Hong
AU - He, Fuliang
AU - Xu, Qinggang
AU - Liu, Lianxin
AU - Li, Min
AU - Zhang, Songhua
AU - Nagaoka, Katsuya
AU - Carlson, Rolf
AU - Safran, Howard
AU - Charpentier, Kevin
AU - Sun, Bei
AU - Wands, Jack
AU - Dong, Xiaoqun
N1 - Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - 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 survival (OS) in PDAC patients (log-rank test, Ps < 0.001; Cox proportional hazards regression, P < 0.001). Therefore, ASPH-Notch axis is essential for propagating multiple-steps of metastasis and predicts prognosis of PDAC patients. A specific SMI targeting ASPH offers a novel therapeutic approach to substantially retard PDAC development/progression.
AB - 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 survival (OS) in PDAC patients (log-rank test, Ps < 0.001; Cox proportional hazards regression, P < 0.001). Therefore, ASPH-Notch axis is essential for propagating multiple-steps of metastasis and predicts prognosis of PDAC patients. A specific SMI targeting ASPH offers a novel therapeutic approach to substantially retard PDAC development/progression.
KW - Aspartate β-hydroxylase (ASPH)
KW - Exosome
KW - Notch
KW - Pancreatic ductal adenocarcinoma (PDAC)
KW - Patient derived xenograft (PDX)
KW - Small molecule inhibitor (SMI)
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U2 - 10.1016/j.canlet.2020.02.039
DO - 10.1016/j.canlet.2020.02.039
M3 - Article
C2 - 32145343
AN - SCOPUS:85083047682
SN - 0304-3835
VL - 481
SP - 63
EP - 75
JO - Cancer Letters
JF - Cancer Letters
ER -