Journal
JOURNAL OF EXTRACELLULAR VESICLES
Volume 10, Issue 11, Pages -Publisher
WILEY
DOI: 10.1002/jev2.12146
Keywords
autophagy; cancer-associated fibroblasts; exosomes; invasion; oxidized ATM
Categories
Funding
- National key projects of Ministry of Science and Technology of China [2018YEE0113700]
- National Natural Science Foundation of China [NSEC81472476, NSEC31671481, 31171336]
- Innovation Research Group in Colleges and Universities Program of Chongqing Municipal Education Commission [CXQI20012]
- Postgraduate Fund of Chongqing Medical University [BJRC202021]
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Studies have shown that oxidized ATM phosphorylates BNIP3 to induce autophagosome accumulation and exosome release in breast CAFs. In addition, oxidized ATM phosphorylates ATP6V1G1, leading to lysosomal dysfunction and facilitating exosome release through fusion with multi-vesicular bodies. This process ultimately stimulates non-canonical NF-kappa B signaling and enhances the invasive abilities of recipient breast cancer cells.
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-kappa B 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.
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