Drug-resistant cancer cell-derived exosomal EphA2 promotes breast cancer metastasis via the EphA2-Ephrin A1 reverse signaling

Zicong Gao,Zhiyong Wang,Yuying Zhu,Yanfen Cui,Xingxing Han,Zhaosong Wang,He Zhang,Ran Tian,Ruifang Niu,Fei Zhang

doi:10.1038/s41419-021-03692-x

Abstract

Tumor metastasis induced by drug resistance is a major challenge in successful cancer treatment. Nevertheless, the mechanisms underlying the pro-invasive and metastatic ability of drug resistance remain elusive. Exosome-mediated intercellular communications between cancer cells and stromal cells in tumor microenvironment are required for cancer initiation and progression. Recent reports have shown that communications between cancer cells also promote tumor aggression. However, little attention has been regarded on this aspect. Herein, we demonstrated that drug-resistant cell-derived exosomes promoted the invasion of sensitive breast cancer cells. Quantitative proteomic analysis showed that EphA2 was rich in exosomes from drug-resistant cells. Exosomal EphA2 conferred the invasive/metastatic phenotype transfer from drug-resistant cells to sensitive cells. Moreover, exosomal EphA2 activated ERK1/2 signaling through the ligand Ephrin A1-dependent reverse pathway rather than the forward pathway, thereby promoting breast cancer progression. Our findings indicate the key functional role of exosomal EphA2 in the transmission of aggressive phenotype between cancer cells that do not rely on direct cell–cell contact. Our study also suggests that the increase of EphA2 in drug-resistant cell-derived exosomes may be an important mechanism of chemotherapy/drug resistance-induced breast cancer progression.

Highlights

Anthracyclines and taxanes-based chemotherapy regimens are very commonly used in the treatment of malignant tumors[1,2,3]
PD98059 blocked the pro-migratory effect of exosomes carrying EphA2 and EphA2-ΔS (Fig. 6k). These results indicated that exosomal EphA2 promoted the aggressive behavior of breast cancer cells by activating the ERK1/2 pathway, which was downstream of EphA2-Ephrin A1 reverse signaling
The primary findings of this study support a model, in which exosomes derived from drug-resistant cells mediate cancer cell–cell communications and promote the invasion and metastasis of sensitive breast cancer cells

Summary

Introduction

Anthracyclines (doxorubicin, epirubicin) and taxanes (paclitaxel, docetaxel)-based chemotherapy regimens are very commonly used in the treatment of malignant tumors[1,2,3]. The failure of chemotherapy is accompanied by the emergence of drug resistance and tumor relapse[7,8,9]. Recent studies have shown that chemotherapy can induce invasiveness and metastasis of breast cancer cells[10,11,12]. Intercellular communications in tumor microenvironment are required for cancer initiation and progression[23,24,25,26]. Tumor cells can transmit or exchange messages with surrounding cells to promote cell proliferation, resistance to drugs, migration, and metastasis to distant organs. Extracellular vesicles, exosomes, have been identified as the important carriers that transmit specific substances to neighboring or distant cells[27,28,29]. Exosome-mediated intercellular communications between cancer cells and stromal

Methods

Results

Conclusion