New research from the US has revealed how a pathway inside cells essential for activating inflammatory immune response is unleashed to prevent cancer formation by detecting DNA damage within cells.
In doing so, the research team discovered the key that unlocks the cGAS/STING pathway, which is normally turned off to prevent excessive inflammation in healthy conditions.
Gaorav Gupta, MD, PhD is associate professor in the Department of Radiation Oncology at the the University of North Carolina (UNC) School of Medicine.
He said: “Our findings suggest that loss of this pathway may be what’s allowing breast cancer cells to withstand high levels of DNA damage without being recognised by the immune system.
“We’re very interested in identifying ways to reactivate this pathway to treat and potentially even prevent cancer development.”
The enzyme cyclic GMP-AMP synthase (cGAS) is well known for its role as a messenger for the immune system.
Double-stranded DNA viruses, such as chickenpox and herpes simplex and DNA-damaged cells are perceived as threats and waste to the body.
In response, cGAS calls on the immune system to seek out the threat and eliminate it from the body.
Robert McGinty, MD, PhD at the UNC Eshelman School of Pharmacy, Pengda Liu, PhD, and Qi Zhang, PhD, of the UNC Department of Biochemistry and Biophysics, were amongsthe first research teams to make a landmark discovery about cGAS.
Their research revealed that cGAS is “locked up” in an effort to prevent the body from unleashing the inflammatory immune response unless it is absolutely necessary.
Gupta said: “It’s in a ‘turned off’ state because it has a much stronger affinity for histones molecules, which are proteins around which our DNA is packaged, than to DNA itself.
“You can think of cGAS as being locked up through its binding to histones, not able to perform its duty to recognise DNA unless it is freed by some key.”
In light of his colleagues’ research, Gupta reached out to them to test a new hypothesis, using the assays they had previously developed and used in those studies.
Gupta’s lab was curious to know whether a protein being investigated in his lab, MRE11, which is known to recognise broken fragments of DNA, may also be the key that releases cGAS from its histone prison.
Indeed, the researchers found that MRE11, in the process of recognising and binding to broken DNA, simultaneously releases cGAS from the histones (proteins that provides structural support for a chromosome).
Min-Guk Cho, PhD is a postdoctoral fellow in Gupta’s lab and co-first author on the paper.
The researcher said: “This was fascinating because MRE11 was known for detecting and repairing DNA damage, but the evidence I uncovered indicated that MRE11 plays a different role, namely in activating the innate immune system.”
Researchers also found that when MRE11 and cGAS interact with one another, they initiate a specialised form of cell death called necroptosis.
As opposed to other forms of cell death, necroptosis causes cells to die in a way that triggers immune activation, making it easier for the body to trigger an all-hands-on-deck effort.
Gupta said: “Linking Mre11 and cGAS to necroptosis activation is a very effective way for suppressing tumour formation.
“When MRE11 and cGAS are activated by a damaged precancerous cell, they cooperate to activate an immune-boosting form of cell death, to help our bodies eliminate the cells before they develop into a cancer.”
Gupta and colleagues in the UNC Lineberger Comprehensive Cancer Center are now enrolling patients for a clinical trial at UNC to examine the combination of radiation and immunotherapy as a means of treating certain types of breast cancer.
With this new information in hand, scientists will see if the pathway is more or less responsive to these therapies, or if specific types of therapies may more effectively engage this pathway and result in improved clinical outcomes.