Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment
Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment
复制标题
外泌体递送的 CD44v6/C1QBP 复合物通过促进肝脏纤维化微环境驱动胰腺癌肝转移
DOI：
10.1136/gutjnl-2020-323014
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发表时间：
2021-04-06
期刊：
影响因子：
24.5
通讯作者：
Zhang, Yi-Fan
中科院分区：
文献类型：
--
作者：
Xie, Zhibo;Gao, Ya;Zhang, Yi-Fan
目的胰腺导管腺癌(PDAC)是肝转移的高发肿瘤。癌前分泌组通过外体传递和运输对于转移前微环境的形成和转移是至关重要的。本研究旨在探讨PDAC衍生的外切体(Pex)调节肝脏微环境和促进肿瘤转移的潜在机制。设计通过尾静脉注射PEX对C57BL/6小鼠进行“教育”。采用脾内注射肝转移模型和PDAC原位移植模型评价肝转移情况。建立了稳定的CD44v6(CD44变异体6)或C1QBP(补体C1q结合蛋白)敲除或过表达的细胞系。对华山医院142例PDAC患者进行了回顾性研究。采用Kaplan-Meier生存曲线和Logistic回归模型预测预后和肝转移。结果Pex尾静脉注射可诱导肝纤维化细胞外基质沉积，促进PDAC肝转移。具体地说，胞外体CD44v6/C1QBP复合体被运送到肝卫星细胞(HSCs)的质膜上，导致胰岛素样生长因子1信号分子的磷酸化，从而导致HSC激活和肝纤维化。Pex CD44v6和C1QBP在有肝转移的PDAC患者中的表达显著高于无肝转移的PDAC患者，且胞外体CD44v6和C1QBP的同时高表达与PDAC术后肝转移的风险和预后有关。结论PEX来源的CD44v6/C1QBP复合体在肝纤维化微环境的形成和PDAC肝转移中起重要作用。CD44v6和C1QBP的高表达可作为预测PDAC患者预后和肝转移的生物标志物。
Objective Pancreatic ductal adenocarcinoma (PDAC) shows a remarkable predilection for liver metastasis. Pro-oncogenic secretome delivery and trafficking via exosomes are crucial for pre-metastatic microenvironment formation and metastasis. This study aimed to explore the underlying mechanisms of how PDAC-derived exosomes (Pex) modulate the liver microenvironment and promote metastasis. Design C57BL/6 mice were ‘educated’ by tail vein Pex injection. The intrasplenic injection liver metastasis and PDAC orthotopic transplantation models were used to evaluate liver metastasis. Stable cell lines CD44v6 (CD44 variant isoform 6) or C1QBP (complement C1q binding protein) knockdown or overexpression was established using lentivirus transfection or gateway systems. A total of 142 patients with PDAC in Huashan Hospital were retrospectively enrolled. Prognosis and liver metastasis were predicted using Kaplan-Meier survival curves and logistic regression models. Results Pex tail vein injection induced the deposition of liver fibrotic extracellular matrix, which promoted PDAC liver metastasis. Specifically, the exosomal CD44v6/C1QBP complex was delivered to the plasma membrane of hepatic satellite cells (HSCs), leading to phosphorylation of insulin-like growth factor 1 signalling molecules, which resulted in HSC activation and liver fibrosis. Expression of Pex CD44v6 and C1QBP in PDAC patients with liver metastasis was significantly higher than in PDAC patients without liver metastasis, and simultaneous high expression of exosomal CD44v6 and C1QBP correlated with a worse prognosis and a higher risk of postoperative PDAC liver metastasis. Conclusion The Pex-derived CD44v6/C1QBP complex is essential for the formation of a fibrotic liver microenvironment and PDAC liver metastasis. Highly expressed exosomal CD44v6 and C1QBP are promising biomarkers for predicting prognosis and liver metastasis in patients with PDAC.