Hypoxia-stimulated ATM activation regulates autophagy-associated exosome release from cancer-associated fibroblasts to promote cancer cell invasion

• Type of Material: Article
• Authors: Lei Xi, Chongqing Medical University; Meixi Peng, Chongqing Medical University; Shuiqing Liu, Chongqing Medical University; Yongcan Liu, Chongqing Medical University; Xueying Wan, Chongqing Medical University; Yixuam Hou, Chongqing Medical University; Yilu Qin, Chongqing Medical University; Liping Yang, Chongqing Medical University; Shanchun Chen, Chongqing Medical University; Huan Zeng, Chongqing Medical University; Yong Teng, Emory University; Xiaojiang Cui, Cedars‐Sinai Medical Center; Manran Liu, Chongqing Medical University
• Language: English
• Date: 2021-09-01
• Publisher: WILEY
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/jev2.12146
• Title of Journal or Parent Work: JOURNAL OF EXTRACELLULAR VESICLES
• Volume: 10
• Issue: 11
• Start Page: e12146
• End Page: e12146
• Grant/Funding Information: This work was supported in part by National key projects of Ministry of Science and Technology of China (MOST 2018YFE0113700), National Natural Science Foundation of China (NSFC81472476, NSFC31671481, and NSFC 31171336), and by Innovation Research Group in Colleges and Universities Program of Chongqing Municipal Education Commission (No. CXQT20012) to Manran Liu.; And also supported by the outstanding Postgraduate Fund of Chongqing Medical University (BJRC202021) for Yongcan Liu.
• Keywords: autophagy; TRANSLOCATION; PROLIFERATION; BNIP3; exosomes; cancer-associated fibroblasts; invasion; PHOSPHORYLATION; Science & Technology; Life Sciences & Biomedicine; KINASE; Cell Biology; oxidized ATM
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Cancer-associated fibroblasts (CAFs) as a predominant cell component in the tumour microenvironment (TME) play an essential role in tumour progression. Our earlier studies revealed oxidized ATM activation in breast CAFs, which is independent of DNA double-strand breaks (DSBs). Oxidized ATM has been found to serve as a redox sensor to maintain cellular redox homeostasis. However, whether and how oxidized ATM in breast CAFs regulates breast cancer progression remains poorly understood. In this study, we found that oxidized ATM phosphorylates BNIP3 to induce autophagosome accumulation and exosome release from hypoxic breast CAFs. Inhibition of oxidized ATM kinase by KU60019 (a small-molecule inhibitor of activated ATM) or shRNA-mediated knockdown of endogenous ATM or BNIP3 blocks autophagy and exosome release from hypoxic CAFs. We also show that oxidized ATM phosphorylates ATP6V1G1, a core proton pump in maintaining lysosomal acidification, leading to lysosomal dysfunction and autophagosome fusion with multi-vesicular bodies (MVB) but not lysosomes to facilitate exosome release. Furthermore, autophagy-associated GPR64 is enriched in hypoxic CAFs-derived exosomes, which stimulates the non-canonical NF-κB signalling to upregulate MMP9 and IL-8 in recipient breast cancer cells, enabling cancer cells to acquire enhanced invasive abilities. Collectively, these results provide novel insights into the role of stromal CAFs in promoting tumour progression and reveal a new function of oxidized ATM in regulating autophagy and exosome release.