Search

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.

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. [ABSTRACT FROM AUTHOR]

Cancer-associated fibroblasts (CAFs) are the predominant cell type in tumor microenvironment (TM) and featured with the distinct energy metabolism reprogramming (EMR) phenotype caused by many factors such as hypoxia and growth factors. The EMR of CAFs plays a key role in biological behaviors of cancer cells including proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT). Recently, accumulative evidence indicates that oxidative stress (OS) mediates the EMR of CAFs under conditions of various stimuli. However, the precise mechanism by which OS causes the EMR of CAFs is not clear. Interestingly, our previous work suggested that ataxia-telangiectasia mutated (ATM) signaling is activated independent of DNA double strand breaks (DSBs) in CAFs derived from human breast cancers compared with paired normal fibroblasts (NFs). Recent studies have shown that ATM protein kinase, as a redox sensor, is closely associated with cellular energy metabolism. Thus, it is very possible that ATM protein kinase regulates the EMR of CAFs. So, it is necessary to perform an integral study on how oxidized ATM regulates the EMR of CAFs in response to various stimuli evoking OS. This will facilitate to develop a new powerful strategy of preventing and treating cancers. [ABSTRACT FROM AUTHOR]