Exosomes Derived From Macrophages Enhance Aerobic Glycolysis and Chemoresistance in Lung Cancer by Stabilizing c-Myc via the Inhibition of NEDD4L.

Huan Wang,Yaona Wang,Haiyan Pan,Lie Wang,Zhijun Chen,Xinfu Pan,Miao Shi,Hang Yu,Chaoye Wang

doi:10.3389/fcell.2020.620603

Abstract

As one of the most common and lethal cancer, lung cancer severely threatens the health of human. It has been reported that tumor-associated macrophages promote initiation, progression, as well as chemoresistance in human cancers. However, the underneath molecular mechanism that drives chemoresistance in lung cancer is yet not fully characterized. In this article, we demonstrated that M2 macrophage-derived exosomes (MDE) is the key factor to promote cisplatin-resistance in lung cancer. MDE exhibited high expression level of several miRNA including miR-3679-5p. Mechanistically, miR-3679-5p was delivered to lung cancer cells by MDE, downregulating the expression of a known E3 ligase, NEDD4L, which has been identified as a key regulator controlling the stability of c-Myc. Such decreased NEDD4L expression level resulted in the stabilization of c-Myc and elevated glycolysis. The enhanced glycolysis drives the chemoresistance in lung cancer. Taken together, our findings not only show that M2 macrophage induce chemoresistance in lung cancer through MDE mediated miR-3679-5R/NEDD4L/c-Myc signaling cascade, but also shed the light on the mechanism of the cross-talk between M2 macrophage and lung cancers. By pinpointing a potential novel survival signaling pathway, our data could provide a new potential therapeutic target for lung cancer treatment and management.

Highlights

Despite the rapid progression in the research of novel therapies, lung cancer remains the most malignant as well as lethal cancer due to relapse and resistance to treatment (Global Burden of Disease Cancer Collaboration et al, 2015; Yuan et al, 2019)
In order to determine the biological function of M2 macrophage in lung cancer tissue, we firstly assessed the status of M2 macrophage in lung adenocarcinoma (LUAD) samples
By determining the expression levels of three major M2 macrophage markers across LUAD samples as well as in adjacent normal control tissues, we found that compared with normal tissues, M2 macrophages were significantly enriched in LUAD tissues (Figure 1A)

Summary

Introduction

Despite the rapid progression in the research of novel therapies, lung cancer remains the most malignant as well as lethal cancer due to relapse and resistance to treatment (Global Burden of Disease Cancer Collaboration et al, 2015; Yuan et al, 2019). One widely accepted hypothesis is that the reprogramming of glucose metabolism causes a wide range of physiological changes, including abnormal DNA repairing, enhanced autophagy, and increased exosomes secretion, in cancer cells (Hay, 2016). One possible mechanism of how TAMs promote cancer metastasis as well as drug resistance is that the survival signals from TAMs were transmitted to cancer cells through macrophage-derived exosomes (MDE). It has been widely reported that exosomes play key tumorigenesis, drug resistance, as well as metastasis by mediating material exchange between tumor and stromal cells (Taylor and Gercel-Taylor, 2011; Luga et al, 2012; Peinado et al, 2012), and between tumor and macrophages (Lan et al, 2019; Yu et al, 2019; Zhu et al, 2019; Kwon et al, 2020). The mechanism of MDE driving chemoresistance in lung cancer is still under investigated

Objectives

Methods

Results

Conclusion