Journal Article

Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment

Gao, Ya, Zhang, Yi-Fan, Li, Lequn, Jin, Chen, Xie, Zhibo, Zou, Caifeng, Wang, Xiaobo, Mao, Yishen, Ho, Chiakang, Wang, Xiaoyi, Li, Qingfeng, Fu, Deliang

2022

Overview

ObjectivePancreatic 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.DesignC57BL/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.ResultsPex 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.ConclusionThe 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.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD
• Subject: Adenocarcinoma / Animals / Apoptosis / Carcinoma, Pancreatic Ductal - mortality / Carcinoma, Pancreatic Ductal - secondary / Carrier Proteins - physiology / CD44 antigen / China / Collagen / Communication / Complement component C1q / Education / Exosomes / Exosomes - physiology / Extracellular matrix / Fibroblasts / Fibrosis / Gene expression / Hepatocytes / Humans / Hyaluronan Receptors - physiology / Injection / Insulin / Insulin-like growth factors / Kaplan-Meier Estimate / Liver / Liver cancer / Liver Cirrhosis - etiology / Liver Cirrhosis - pathology / liver metastases / Liver Neoplasms - mortality / Liver Neoplasms - secondary / Logistic Models / Metastases / Metastasis / Mice / Mice, Inbred C57BL / Microenvironments / Mitochondrial Proteins - physiology / molecular oncology / Pancreas / Pancreatic cancer / Pancreatic Neoplasms - mortality / Pancreatic Neoplasms - pathology / Patients / Phosphorylation / Prognosis / Proteins / Quantitative analysis / Regression analysis / Retrospective Studies / Satellite cells / Secretome / Transfection / Transplantation / Tumor Microenvironment / Tumors