Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis
Prometastatic secretome trafficking via exosomes initiates pancreatic cancer pulmonary metastasis
复制标题
通过外泌体进行转移性分泌组运输引发胰腺癌肺转移
DOI：
10.1016/j.canlet.2020.02.039
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发表时间：
2020-07-01
期刊：
影响因子：
9.7
通讯作者：
Dong, Xiaoqun
中科院分区：
文献类型：
--
作者：
Ogawa, Kosuke;Lin, Qiushi;Dong, Xiaoqun
为了从多方面阐明天冬氨酸-β-羟基酶(ASPH)在胰腺导管腺癌(PDAC)发病机制中的作用，建立了体外转移实验和患者源性异种移植(PDX)小鼠模型。ASPH传播侵袭性表型，其特征是增强的上皮-间充质转化(EMT)、2-D/3-D侵袭、细胞外基质(ECM)降解/重塑、血管生成、茎突、跨内皮细胞迁移和远处转移的定植/生长。从机制上讲，ASPH通过与Notch1/Jags和Adams的直接物理相互作用来激活Notch级联。ASPH-Notch轴使转移前的分泌物通过外体运输，随后启动MMPs介导的ECM降解/重塑，作为侵袭性的效应器。因此，在PDX模型中，ASPH促进了原发肿瘤的发展和肺转移，这被一种新开发的针对ASPH的β-羟基酶活性的小分子抑制剂(SMI)所阻断。在临床上，ASPH在正常胰腺中是沉默的，从癌前病变逐渐上调到侵袭性/晚期PDAC。相对较高水平的ASPH-Notch网络成分独立/联合预测PDAC患者缩短的总存活率(LOG-RANK检验，P&t；0.001；COX比例风险回归，P<；0.001)。因此，ASPH-Notch轴在预测PDAC患者的多步骤转移和预后方面是必不可少的。针对ASPH的特异性SMI提供了一种新的治疗方法，可以显著延缓PDAC的发展/进展。
To demonstrate multifaceted contribution of aspartate beta-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 beta-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.