Metastatic cells establishing themselves in distant organs experience a vulnerable transient phase known as a “proliferative pause,” according to a study published in Cancer Cell. Led by the Brain Metastasis Group at the Spanish National Cancer Research Centre (CNIO), researchers discovered that this previously unknown adaptive stage makes micrometastases susceptible to elimination using three existing drugs, two of which are already approved for other indications.
Uncovering the Proliferative Pause in Brain Metastases
Metastasis accounts for the majority of cancer deaths. When cancer cells originating from tumors in organs like the breast, lung, or skin colonize the brain, they encounter a hostile environment. Many cells die during this transition, but those that survive enter a period of relative inactivity called a “proliferative pause.” During this stage, the tumor cells adapt to their new surroundings while temporarily abandoning aggressive behavior.
Manuel Valiente, head of CNIO’s Brain Metastasis Group, led the research effort that began more than six years ago involving more than 70 co-authors from roughly 20 institutions across Spain, the United Kingdom, Germany, France, and the United States. “When we analyzed the biology of these micrometastases, which are still clinically undetectable, we identified the molecular mechanisms that were active,” Valiente stated. Because existing drugs target these exact molecules, the team tested three of them in animal models, successfully eliminating the micrometastases before they could develop into detectable tumors.
Validation Through Human Autopsy and Surgery Samples
To confirm the findings observed in mice, the CNIO team utilized human tissue samples provided by two major research consortia. Autopsy samples from the UK-based PEACE consortium proved essential, as autopsies are the only way to identify micrometastases. Mariam Jamal-Hanjani, chief investigator of the PEACE study at the UCL Cancer Institute, noted that the research has the potential to transform clinical intervention. “This study has the potential to transform our ability to intervene with targeted drugs to prevent the progression of microscopic cancer in the brain,” Jamal-Hanjani said.
Following validation through PEACE, the research team tested treatments in living human samples via the Spanish RENACER consortium, the National Brain Metastasis Network founded by Valiente in 2021. RENACER supplies metastatic tissue removed during neurosurgery from fully developed metastases. The analysis revealed that the molecular processes active during the vulnerable phase of micrometastases closely resemble those found at the leading edge, or invasive front, of established metastases where cells spread by attaching to surrounding blood vessel walls.
Implications for Preventing Post-Surgical Relapse
The discovery that the vulnerabilities of early micrometastases mirror those found at the invasive fronts of larger tumors points toward a new therapeutic strategy. According to Valiente, this overlap suggests that clinicians can target the same mechanisms to stop the invasive fronts of human metastases. “This finding suggests that we can turn the problem around and test preventive therapies in a clinically relevant situation where there is currently no clear therapeutic strategy: preventing relapse after surgery,” Valiente explained.
While the study opens up strategies to prevent metastasis from recurring after surgery or tackling the disease before symptoms appear, immediate clinical application faces hurdles. Currently, no diagnostic tests can detect micrometastases, and reliable biomarkers to identify patients at risk do not yet exist. The CNIO group’s medium-term objective is to launch clinical trials, focusing first on determining which drug combinations yield the highest therapeutic benefit alongside biomarker identification efforts.
Collaborative Research Network Behind the Study
The findings published in Cancer Cell relied on a broad international framework. Participating institutions included the National Centre for Genomic Analysis (CNAG) in Barcelona for single-cell analyses, the US National Cancer Institute (NCI) and UT Southwestern Medical Center for metastatic brain disease models, the Technical University of Dresden for protein mapping, the Instituto de Neurociencias (CSIC-UMH) in Alicante for video-microscopy, the University of Cantabria for electron microscopy, the Francis Crick Institute and University College London via the PEACE consortium, and the Universities of Oxford and Castilla-La Mancha for mathematical modeling.
Cancer cells halt aggressive behavior to survive hostile new environments
What is a proliferative pause in cancer metastasis?
It is a newly discovered transient adaptive stage where cancer cells that have successfully reached a distant organ halt aggressive behavior to survive a hostile new environment.
Can these micrometastases be treated currently?
Not yet in a preventative clinical setting. While researchers have eliminated micrometastases in animal models using three drugs—two of which are already approved for other uses—doctors currently lack diagnostic tests to detect micrometastases or biomarkers to identify patients at risk before symptoms appear.
What role did the PEACE consortium play?
The PEACE consortium provided post-mortem tumor repository samples, allowing researchers to study undetected human brain micrometastases and validate molecular mechanisms discovered in animal models.