Every time cancer cells divide, they cause damage to their own DNA molecules. For a long time, scientists including Gao á v Gupta Bo, associate professor of radiation oncology at the University of North Carolina School of Medicine in the United States, have been curious about how cancer can evade detection by the body’s own defense system, despite the immune system constantly monitoring cells for DNA damage.
In a new study, Gupta’s laboratory revealed how the cGAS/STING pathway – a necessary pathway for activating inflammatory and immune responses within cells – can prevent cancer formation by detecting DNA damage within cells. During this process, they discovered the “key” to “opening” the cGAS/STING pathway, as in healthy conditions, the cGAS/STING pathway is usually closed to prevent excessive inflammation. The relevant research results were published online in the journal Nature, under the title “MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis”.
Gupta said, “Our research results show that the loss of this pathway may be the reason why breast cancer cells can withstand high levels of DNA damage without being recognized by the immune system. We are very interested in finding ways to reactivate this pathway to treat and even prevent cancer development.”
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Release the key to cGAS
An enzyme called cyclic GMP-AMP synthase (cGAS) is widely known for its role as a messenger molecule in the immune system. Double stranded DNA viruses (such as herpes simplex virus and chickenpox virus) and cells with damaged DNA are considered a threat and waste to the human body. In response, the task of cGAS is to call on the immune system to search for threats and eliminate them from the body.
As early as 2020, research teams such as Dr. Robert McGinty from the Escherman School of Pharmacy at the University of North Carolina, Dr. Pengda Liu and Dr. Qi Zhang from the Department of Biochemistry and Biophysics at the University of North Carolina were the first to discover cGAS. Their paper published in the Science journal showed that cGAS is “locked up” to prevent the body from activating inflammatory immune responses when not necessary (Science, 2020, doi:10.1126/science.abd0609).
Gupta said, “The reason it is in a ‘closed’ state is because its affinity with histone molecules is much stronger than its affinity with DNA itself. You can imagine cGAS being locked in by binding to histones, unable to fulfill its duty of recognizing DNA, unless it is released through some kind of key.”
Given the findings of Gupta colleagues, Gupta contacted them in the hope of using the detection methods they had previously developed and used in these studies to validate a new hypothesis. Gupta’s laboratory is curious to know if a protein called MRE11, which is known to recognize broken DNA fragments, may also be the key to releasing cGAS from histone prisons. In fact, they found that MRE11 releases cGAS from histones while recognizing and binding to broken DNA.
Dr. Min Guk Cho, co-first author of the paper and postdoctoral researcher at Gupta Laboratory, said, “This is fascinating because MRE11 is known for detecting and repairing DNA damage, but the evidence I have found suggests that MRE11 plays a different role in activating the innate immune system.”
The relationship between inflammation and cell death
These authors also found that when MRE11 interacts with cGAS, they initiate a special form of cell death – necroptosis. Unlike other forms of cell death, necroptosis leads to cell death in a way that triggers immune activation, making it easier for the body to initiate collective action.
Gupta said, “Linking Mre11 and cGAS with activation of necroptosis is a highly effective method for inhibiting tumor formation. When MRE11 and cGAS are activated by damaged precancerous cells, they cooperate to activate an immune enhancing form of cell death, helping our body eliminate them before they develop into cancer.”
Future clinical treatment and collaboration
Gupta and colleagues from the Lindbergh Comprehensive Cancer Center at the University of North Carolina are actively recruiting patients to participate in a clinical trial to study how to combine radiotherapy and immunotherapy as a means of treating certain types of breast cancer.
With this new information, scientists will understand whether the cGAS/STING pathway responds strongly or weakly to these therapies, or whether specific types of therapies can more effectively intervene in this pathway and improve clinical outcomes.
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Reference
Min-Guk Cho et al. MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis. Nature, 2024, doi:10.1038/s41586-023-06889-6.