The metastasis It is the spread of cancer cells from the original tumor to other organs and tissues in the body and is considered the leading cause of death in cancer patients. Now a path of hope opens for those affected by lung cancersince a group of researchers from the Sloan Kettering Institute has discovered that the STING cell signaling pathway it may be a key element in preventing hidden cancer cells from developing into aggressive cancer months or even years after escaping from a primary tumor.
These scientists have carried out a study whose results have been published in Nature and suggest that drugs capable of activating STING could help prevent the spread of cancer cells throughout the body. Specifically, they found that treatment that stimulated the STING pathway helped kill cancer cells and prevented them from becoming aggressive metastases in a mouse model of lung cancer.
“Anything we can do to prevent these cells from waking up again or to help the immune system kill 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 metastases,” said Joan Massagué, lead author of the study and director of the Sloan Kettering Institute, a center for basic science and translational research within the Center for Memorial Sloan Kettering (MSK) Cancer.
Advances in new treatments to stop metastasis
To carry out the study, they focused on the earliest phases after the development of cancer, before it has been able to successfully spread to other parts of the body, explained Jing Hu, senior research scientist at Massagué Lab and first author of the work. “For example, almost half of patients diagnosed with stage 1 or stage 2 lung adenocarcinoma will develop metastases,” she says. “By the time of diagnosis, we believe that many of these patients will already have escaped some cancer cells from their primary tumor and will travel to other organs, where they will lie dormant until they wake up and generate what we call spontaneous cancer or breakthrough metastases”.
The STING cell signaling pathway plays a key role in recruiting immune cells that attack cancer cells and prevent metastasis
Many of the cancer cells that break away from a primary tumor die as they travel to distant organs, but those that survive learn to adapt to the human body. “Tumor cells are not in a welcoming environment at first,” Hu says, “so they have to adapt and develop their own self-sustaining niche until they are ready to wake up and start a fast-growing metastasis. The interaction with the person’s immune system is very important in this process.”
The researchers used mouse models of early-stage metastasis of lung cancer to perform genetic screening to observe the activity of genes in tumor cells that are important for interactions with the host’s immune system, allowing them to identify the via STING, an acronym for interferon gene stimulator, as a metastatic sprout suppressor.
They found that STING expression varies at different stages of metastasis. In the latent stage, STING activity is low, and dormant cells hide from immune defenses. Upon exiting the inactive phase, metastatic cells begin to have increased STING activity, making them more vulnerable to attack by the immune system. Those that survive, however, spawn larger groups called macrometastases that have 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,” says Dr. Massagué. “The use of STING activators in conjunction with this window of increased STING activity in reactivated cancer cells could be an opportunity to help the body’s immune defenders destroy them.”
So when the scientists boosted STING signaling in those aggressive metastatic cells artificially, more immune defenders, such as natural killer cells and T cells, came to kill them off. And when they turned on STING in mice without key immune cells, they did metastases developed, indicating that STING plays a critical role in recruiting immune cells to attack cancer cells.
To see if their findings could apply to humans, the researchers compared their observations in mouse models with small numbers of cancer cells from the lymph nodes of early-stage lung cancer patients, and what they observed in the patients supported what they had found in the laboratory.
Dr. Hu has highlighted that drugs that increase STING activity they are called STING agonists and they are already being evaluated in some clinical trials, but those trials are intended for patients with advanced cancers, when they have already developed aggressive metastases and the tumor cells have already transformed their immediate environment to better protect themselves against the attacks of the host immune system. “In the early stages of metastasis, STING agonists may have a greater effect,” Hu says. “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 increased.”
The researchers’ goal is to collaborate with physicians to conduct a clinical trial that will look in detail at the vulnerabilities of micrometastases in patients with newly discovered early-stage cancer. One possibility would be to take advantage of STING to kill malignant cells before they metastasize, and another alternative could be to try to keep cells dormant forever.