Inhibition of AURKA kinase activity suppresses collective invasion in a microfluidic cell culture platform

Jiang-Long Xia,Chun-Li Wang,Wen-Wen Zhang,Meng-Ying Yang,Jia-Jun Xie,Hong-Ming Teng,Muhammad Kamran,Wen-Jun Fan,Peng Wang,Fei-Meng Zheng,Quentin Liu

doi:10.1038/s41598-017-02623-1

Abstract

Tumor local invasion is the first step of metastasis cascade which remains the key obstacle for cancer therapy. Collective cell migration plays a critical role in tumor invading into surrounding tissues. In vitro assays fail to assess collective invasion in a real time manner. Herein we aim to develop a three-dimensional (3D) microfluidic cell invasion model to determine the dynamic process. In this model, collective invasion of breast cancer cells is induced by the concentration gradient of fetal bovine serum. We find that breast cancer cells adopt a collective movement rather than a random manner when the cells invade into extracellular matrix. The leading cells in the collective movement exhibit an increased expression of an Aurora kinase family protein - AURKA compared with the follower cells. Inhibition of AURKA kinase activity by VX680 or AKI603 significantly reduces the phosphorylation of ERK1/2 (Thr202/Tyr204) and collective cohort formation. Together, our study illustrates that AURKA acts as a potential therapeutic target for suppressing the process of tumor collective invasion. The 3D microfluidic cell invasion model is a reliable, measurable and dynamic platform for exploring potential drugs to inhibit tumor collective invasion.

Highlights

Tumor metastasis has caught extensive attention for decades since it explains 90 percent of tumor patients mortality[1]
We revealed that AURKA was a critical regulator for collective invasion in the leader cells, which guided the formation of collective cohorts
The invasion distance and overall invasion area were effectively inhibited in AKI603 and VX680 groups (Fig. 5D,E). These results suggested that AKI603 and VX680 effectively suppressed tumor collective invasion in a 3D environment

Summary

Introduction

Tumor metastasis has caught extensive attention for decades since it explains 90 percent of tumor patients mortality[1]. A group develops a transendothelial invasion-model contained the basic components of blood vessels, such as vessel cavity, endothelium, and perivascular ECM containing chemokines In this device, salivary gland adenoid cystic carcinoma (ACC) cellular aggregates transmigrated across the endothelium with the stimulation of CXCL1213. Salivary gland adenoid cystic carcinoma (ACC) cellular aggregates transmigrated across the endothelium with the stimulation of CXCL1213 In another 3D in vitro microfluidic model, an osteo-cell conditional microenvironment is generated to analyze the extravasation of highly metastatic breast cancer cells into an organ-specific site[14]. AURKA was demonstrated to upregulate the expression of matrix metalloproteinase-2 (MMP2) by promoting the activity of p38 MAPK and Akt protein kinases in esophageal squamous cell carcinoma (ESCC)[19] These studies suggest that AURKA could be a promising target for anti-metastasis treatment. Whether AURKA involves in tumor local invasion remains elusive

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