Researchers at the Spanish National Cancer Research Centre (CNIO) have discovered a previously unknown stage in the formation of brain metastases. They found that after reaching a new organ, cancer cells temporarily stop actively multiplying and adapt to their new environment. During this period, they are particularly vulnerable to drug treatment.
The study was published in the journal Cancer Cell. The research, which lasted more than six years, involved more than 70 scientists from around 20 research institutions in Spain, the United Kingdom, Germany, France, and the United States.
Metastasis — the process by which tumor cells spread from the original tumor to other organs — is responsible for most cancer-related deaths. However, the early stages of metastasis formation remain poorly understood: micrometastases that develop in a new organ are too small to be detected by current diagnostic methods.
The researchers studied what happens to cancer cells after they reach the brain. The new organ represents a completely different and unfavorable environment for them, so many cells die. Those that survive enter a state the researchers called a proliferative pause.
During this period, the cells temporarily abandon their aggressive behavior and focus on adapting to their new environment. Experiments showed that this particular feature makes developing micrometastases vulnerable.
The scientists identified the molecular processes that help the cells survive the adaptation period and then tested three drugs that target the corresponding molecular pathways. In experiments in mice, all three drugs eliminated micrometastases before they developed into clinically detectable tumors. Two of the three drugs are already approved for other medical uses.
The researchers further validated the findings using human tissue samples. Particularly important were samples from the UK-based PEACE consortium, which stores tumor tissue obtained during autopsies of patients. Such material makes it possible to detect micrometastases that went unnoticed during patients’ lifetimes because of their small size.
The scientists then confirmed the molecular features they had identified in samples from patients with established metastases from the Spanish RENACER consortium.
The study may also have implications for preventing tumors from returning after surgery. The researchers found that the processes characteristic of the vulnerable stage of micrometastasis formation are similar to those occurring at the edges of established metastases — areas where tumor cells continue to spread along the walls of blood vessels.
As a result, the drugs that proved effective against micrometastases in experiments were also able to stop the activity of such areas of human metastases under laboratory conditions.
However, the findings do not yet mean that metastases can be prevented or treated in patients in this way. Micrometastases cannot currently be reliably detected with existing diagnostic methods, and the effectiveness of the drugs still needs to be tested in clinical trials.
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