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Potential Approach To Combat Cancer Metastasis Identified

This microscope image shows how lung cancer cells invade surrounding tissues and start to spread (metastasize). The depicted lung cancer cells have a mutation of a gene called LKB1 (green) that promotes invasion. Actin, a cytoskeletal protein, is in red, and the cell nucleus is blue.
This image shows how lung cancer cells invade surrounding tissues and start to spread (metastasize). Credit: National Cancer Institute/Winship Cancer Institute of Emory University

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A new study has identified the role of a cell signaling pathway in preventing dormant cancer cells from forming aggressive tumors months, or even years, after escaping from their original tumor. The research is published in Nature.

Putting the brakes on cancer metastasis

During cancer treatment, cells that have broken away from the original – or primary – tumor can escape the immune system by entering a dormant state. The dormant cells can persist for several years, and once they have developed new characteristics to aid their survival, they can reactivate and initiate new tumor growth.

In the current study, researchers investigated cells in the early stage of cancer development before it spreads (metastasizes) instead of focusing on late-stage disease, as advanced tumors may have already formed large, aggressive metastases.

“The tumor cells are not in a supportive environment at the beginning,” said the study’s lead author Dr. Jing Hu. “So they have to adapt and develop their own self-supporting niche until they’re ready, eventually, to wake up and start a fast-growing metastasis. The interaction with the person’s immune system is very important to this process.”

“For example, nearly half of patients diagnosed with stage one or stage two lung adenocarcinoma will develop metastases,” she said. “At the time of diagnosis, we believe many of those patients will already have had some cancer cells break away from their primary tumor and travel to other organs, where they will stay in a dormant state until they wake up and generate what we call spontaneous or breakthrough metastases.”

A STING in the tail

The researchers used mouse models of lung cancer with early-stage metastases to investigate the role of these dormant, disseminated cancer cells. The mice were genetically screened to identify genes involved in interactions with the host’s immune system and measure their activity.

They found that the expression of genes in the STING pathway – an acronym of “stimulator of interferon genes” – changed throughout metastasis, suggesting that STING has a role in suppressing metastasis.

“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,” added Hu.

Dormant cells were found to have low STING activity, enabling them to evade detection by the immune system. When these cells “wake up” and begin to grow and proliferate again, their STING activity also increases – putting them in danger of immune destruction.

However, some activated cells manage to slip through the immune system’s net and survive. These can go on to form large macrometastases, which in turn reduce their STING activity once more and are more resistant to immune attack.

“This means that these tumor cells will be recognized differently by the immune system at different stages of metastasis development,” explained Professor Joan Massagué, senior author of the study. “Using STING activators in conjunction with that window of increased STING activity in the reawakened cancer cells could be an opportunity to help the body’s immune defenders destroy them.”

Massagué and colleagues did just that and artificially increased STING signaling in the aggressive, metastatic cells, attracting immune cells to destroy them. This confirmed the crucial role of immune cells in this mechanism, as activating STING in mouse models that lacked key immune cells could not prevent the formation of metastasis.

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The researchers were also able to confirm the findings gathered from the mouse models to human cells, making similar observations using a small number of cancer cells taken from the lymph nodes of patients with early-stage lung cancer.

Future trials in early disease?

Hu remarks that STING agonists – drugs that increase the activity of the STING pathway – are currently under assessment in clinical trials, though only for patients with advanced cancers. “At the earlier stages of metastasis, STING agonists may be able to have a better effect,” said Hu. “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.”

In the future, the researchers hope to formulate plans for a clinical trial to test the efficacy of these drugs in early-stage disease to either destroy them before they metastasize, or to ensure dormant cells remain inactivated.

“There is a lot more work to be done before these new insights might be applied in the clinic,” said Massagué. “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.”

Reference: Hu J, Sánchez-Rivera FJ, Wang Z, et al. STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma. Nature. 2023:1-8. doi: 10.1038/s41586-023-05880-5

This article is a rework of a press release issued by Memorial Sloan Kettering Cancer Center. Material has been edited for length and content.

Meet the Author
Sarah Whelan, PhD
Sarah Whelan, PhD
Science Writer