A team of scientists from the Sloan Kettering Institute (USA), led by the Spanish researcher Joan Massagué, has identified a key element to prevent latent cancer cells from becoming aggressive tumors months, or even years, after having escaped of a primary tumor.
The element in question is called the cell signaling pathway. STINGand according to the researchers whose study is published in “Nature”, drugs targeting the activation of STING could help prevent the spread of cancer to new sites throughout the body, that is, metastasis.
In mouse models of lung cancer, treatment that stimulated the STING pathway helped kill persistent cancer cells and prevented them from progressing to aggressive metastases. known as micrometastasisthese cells, which can be found singly and in small groups, are too small to be detected with standard imaging tests.
«Most cancer deaths are caused by metastasis“, says Massagué, director of the Sloan Kettering Institute, therefore, “anything we can do to prevent these cells from waking up again or to help the immune system eliminate them could be of great benefit to many people.”
Even when a primary cancer is successfully treated, the cells that have broken away from the tumor often remain in the body in a dormant state that allows them to be invisible to the immune system for years. But, once the dormant cells have developed new traits to survive, they can wake up and begin their rampant growth again.
Instead of focusing on the late stage of the disease, when large, aggressive metastases have already arisen, the researchers did so on the earliest, after the cancer has developed but before it has been able to successfully gain a foothold in new ones. parts of the body, explain Jing Hufirst author of the “Nature” study.
“For example, almost half of patients diagnosed with stage 1 or stage 2 lung adenocarcinoma will develop metastases,” Hu said. At the time of diagnosis, we believe that many of these patients will have already escaped some cancer cells from their primary tumor and will travel to other organs, where they will lie dormant until they wake up and cause what we call spontaneous cancer or breakthrough metastases. ».
Most cancer deaths are caused by metastasis
John Massagué
Director del Instituto Sloan Kettering
Many of these cancer cells that break away from a primary tumor will die during their journey through the bloodstream to remote organs. But those that survive learn to adapt to the body’s defenses.
Using mouse models of early metastasis of lung cancer, the research team performed a genetic screen to observe the activity of genes in tumor cells that are important for interactions with the host’s immune system. This is how they identified the STING pathway, an acronym for interferon gene stimulator, as a suppressor of metastatic sprouting.
“This made a lot of sense to us because STING signaling is known to be important in triggering an immune response against cells made sick by viruses or by cancer mutations,” adds Hu.
most vulnerable
The researchers found that STING expression changes at different stages of metastasis: in the latent phase, it is low, and dormant cells excel at hiding from immune defenders, but exit the inactive stage and enter a proliferative stage. wake up, metastatic cells they begin to have increased STING activity. This makes them more vulnerable to attack by the immune system.
But cells that survive this bottleneck to generate larger clumps, called macrometastases, again show reduced levels of STING, making them more resistant to the immune system.
«This means that these tumor cells will be recognized differently by the immune system at different stages of metastasis development.», explains Massagué.
Therefore, he adds, “the use of STING activators in conjunction with such a window of increased STING activity in reactivated cancer cells could be an opportunity to help the body’s immune defenders destroy them.”
In fact, when the scientists artificially increased STING signaling in these metastatic cells, they attracted more immune defenders, such as natural killer cells and T cells, that swung in to kill them.
In the early stages of metastasis, STING agonists may have a better effect.
Jing Hu
Instituto Sloan Kettering
To check the applicability of their findings, they compared their observations in mouse models with small numbers of cancer cells found in the lymph nodes of early-stage lung cancer patients. What they saw in the patients supported what they were finding in the lab.
Drugs that increase the activity of STING, known as STING agonists, are already being tested in some clinical trials. But those trials are carried out in patients with advanced cancers, when aggressive metastases have already arisen. By then, the tumor cells have already reformed their local environment to better protect themselves from attacks by the host’s immune system.
In person
“In the early stages of metastasis, STING agonists may have a better effect,” Hu said. At that point, the tumor has not yet fully established an immune evasion microenvironment on its own, and STING signaling within tumor cells will be enhanced.”
The researchers hope to collaborate with clinicians to develop a clinical trial targeting the newly discovered vulnerabilities of micrometastases in patients with early-stage disease.
One approach would be to take advantage of STING to kill cells before they can start metastasizing. Another possibility could be to try to keep cells dormant forever.