The role of oxidized ATM in the regulation of oxidative stress-induced energy metabolism reprogramming of CAFs

• EMR is employed by CAFs to promote tumorigenesis in many cancers.
• OS mediates the EMR phenotype of CAFs induced by diverse stimuli in TM.
• Oxidized ATM may promote the EMR of CAFs through phosphorylating its substrates.
• The impact of oxidized ATM on the EMR of CAFs can be exploited to control cancers.

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.