Researchers at the University of North Carolina School of Medicine have identified a crucial mechanism in the cGAS-STING pathway that could unlock new avenues for breast cancer prevention and treatment. Published in Nature, the study sheds light on how cancer cells avoid detection by the immune system, despite sustaining DNA damage during cell division.
The cGAS-STING pathway, responsible for activating the inflammatory immune response, is typically kept in check to prevent excessive inflammation in healthy conditions. However, the study findings showed that breast cancer cells can “lock” this pathway to their advantage, allowing them to escape immune detection.
“Our findings suggest that the loss of this pathway may be enabling breast cancer cells to withstand high levels of DNA damage without being recognized by the immune system,” said Gaorav Gupta, MD, PhD, associate professor in the Department of Biochemistry and Biophysics and a member of UNC Lineberger Cancer Center. “We’re very interested in identifying ways to reactivate this pathway to treat and potentially even prevent cancer development.”
The focal point of the discovery is an enzyme known as cyclic GMP-AMP synthase (cGAS), recognized as a messenger for the immune system. The enzyme is “locked up” in a dormant state, with a higher affinity for histone molecules, which are proteins around which DNA is packaged, rather than DNA itself. Gupta compared cGAS to being “locked up through its binding to histones, not able to perform its duty to recognize DNA unless it is freed by some key.”
Building on earlier research published in Science the team hypothesized that MRE11, a protein known for recognizing broken DNA fragments, might be the key that releases cGAS from its histone prison. During the course of their study, the researchers found that MRE11, while recognizing and binding to broken DNA, simultaneously releases cGAS from the histones.
Min-Guk Cho, PhD, a postdoctoral fellow in Gupta’s lab and co-first author on the paper, expressed excitement about the findings, stating, “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.”
Moreover, the study revealed that the interaction between MRE11 and cGAS triggers a specific form of cell death called necroptosis. This unique form of cell death activates the immune system, providing a powerful mechanism to eliminate damaged precancerous cells before they progress into cancer.
Gupta and his colleagues at the UNC Lineberger Comprehensive Cancer Center are taking this groundbreaking research a step further. They are actively enrolling patients for a clinical trial to investigate the combination of radiation and immunotherapy for treating certain types of breast cancer. The researchers aim to determine the responsiveness of the newly identified pathway to these therapies and explore potential improvements in clinical outcomes.
The scientists hope that their discovery will open new possibilities for developing targeted therapies to reactivate the cGAS-STING pathway, offering hope for more effective breast cancer prevention and treatment strategies in the future.
