Chemoresistance Transmission via Exosome-Transferred MMP14 in Pancreatic Cancer.

Xinyuan Li,Mengmeng Li,Huanjie Yang,Kai Li,Xiaoyu Lin,Xuemei Huang,Yu Mei

doi:10.3389/fonc.2022.844648

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Gemcitabine is the most commonly used chemotherapy for the treatment of PDAC, but the development of drug resistance still remains challenging. Recently, exosomes have emerged as important mediators for intercellular communication. Exosomes affect recipient cells’ behavior through the engulfed cargos, however the specific cargos responsible for gemcitabine resistance in PDAC are poorly understood. Here, we reported that exosomes could transfer gemcitabine resistance via a metalloproteinase 14 (MMP14)-dependent mechanism. MMP14 was identified as a major differentially secreted protein from the gemcitabine-resistant PDAC cells by comparative secretome. It was packaged into the exosomes and transmitted from the chemoresistant cells to the sensitive ones. The exosome-transferred MMP14 could enhance drug resistance and promotes the sphere-formation and migration abilities of the recipient sensitive PDAC cells. Mechanically, exosome-transferred MMP14 promotes the stability of CD44, the cancer stem cell marker in the recipient cells. Our results indicate that MMP14 is a key player for exosome-mediated transfer of gemcitabine resistance, thus targeting MMP14 in exosomes may represent a novel strategy to limit gemcitabine resistance in PDAC.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is a devastating human malignancy with an average 5year survival rate less than 8% [1, 2]
Analysis of subfunctional pathways involved in cell adhesion system indicated that Matrix metalloproteinase 14 (MMP14) was related with the regulation of cell-matrix adhesion and other functional pathways (Figure 1E; Supplementary Figure 1C), indicating that MMP14 is a predominant protein secreted from chemoresistant cells in comparison with the sensitive cells
The current study demonstrates that exosome-transferred MMP14 is one of the reasons responsible for gemcitabine resistance in PDAC cells

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a devastating human malignancy with an average 5year survival rate less than 8% [1, 2]. Most PDAC patients are diagnosed with advanced disease, which are not suitable for surgical resection [3]. Gemcitabine represents the first-line treatment of PDAC, but drug resistance is a major obstacle in improving the patient’s response [4]. Exosomes have emerged as important mediators for cell-to-cell communication [5]. Tumor-derived exosometransferred lncARSR has been reported to transmit sunitinib resistance from drug resistant cancer cells to sensitive ones [7]. Exosome-mediated EphA2 transmission transfers gemcitabine resistance in PDAC [8]. Exosomes shed from tumor microenvironment were found to promote the stemness, epithelial-mesenchymal transition (EMT), metastasis and chemotherapy resistance of cancer cells [9, 10]

Methods

Results

Conclusion