Researchers at Memorial Sloan Kettering Cancer Center have discovered that the STING cellular signaling pathway plays a key role in preventing dormant cancer cells from progressing into aggressive tumors after they’ve escaped from a primary tumor.

The findings are published in Nature in a paper titled, “STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma.”

“Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumor,” wrote the researchers. “These cells fluctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination. Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumor-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak.”

“The majority of cancer deaths are caused by metastasis,” explained Joan Massagué, PhD, the study’s senior author and director of the Sloan Kettering Institute. “Anything we can do to keep these cells from waking up again or to help the immune system eliminate them could be of great benefit to many people. This research identified a previously unknown role for STING signaling in suppressing the development of aggressive metastasis.”

The researchers focused on earlier stages—after cancer has developed but before it has been able to successfully gain a foothold in new parts of the body, said Jing Hu, PhD, a senior research scientist in the Massagué Lab and the first author of the study.

Using mouse models of early-stage metastasis from lung cancer, the research team conducted a genetic screen to look at the activity of genes in the tumor cells that are important for interactions with the host’s immune system.

They identified the STING pathway as a suppressor of metastatic outbreaks.

“This made a lot of sense to us because STING signaling is known to be important for triggering an immune response against cells made sick by viruses or by cancer mutations,” Hu added. The researchers also found that STING expression changes across different stages of metastasis.

When scientists artificially increased STING signaling in aggressive metastatic cells, they attracted more immune defenders like natural killer cells and T cells. When the scientists activated STING in mice lacking key immune cells, metastasis still developed.

The team also identified a new role for the signaling molecule TGF-beta in suppressing STING activity during the dormant stage of metastasis.

“At the earlier stages of metastasis, STING agonists may be able to have a better effect,” Hu said. “At that point, the tumor has not yet fully established an immune-evading microenvironment for itself, and STING signaling within the tumor cells will be higher.”

The researchers hope to collaborate with clinicians to develop a clinical trial to target micrometastases’ newly discovered vulnerabilities in patients with early-stage disease.

The Massagué lab is continuing to explore STING agonists’ ability to destroy lingering metastatic cells.

“There is a lot more work to be done before these new insights might be applied in the clinic,” Massagué said. “But we are encouraged that these efforts and others are bringing us closer to the day when we can prevent many more cancer deaths from metastasis.”

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