• Researchers have discovered a window of opportunity to eliminate metastasis at an early stage, before it causes symptoms.
• The finding opens a potential route to stopping the disease before it becomes clinically apparent, effectively paving the way towards prevention. A similar strategy could also be used to prevent relapse after surgery.
• The study was led by the Brain Metastasis Group at the Spanish National Cancer Research Centre (CNIO), with contributions from around ten Spanish institutions and a similar number of centres in the United Kingdom, Germany, France and the United States.
• “This is the beginning of the race to prevent metastasis,” says CNIO researcher Manuel Valiente, who led the study. Identifying a stage at which the seeds of metastasis are vulnerable “opens a window of opportunity to attack the disease before symptoms appear”.
• The findings are published in Cancer Cell .
Metastasis, the process by which a tumour spreads throughout the body, is associated with the majority of cancer deaths. The Brain Metastasis Group at the Spanish National Cancer Research Centre (CNIO) has investigated the earliest stages in which metastatic cells establish themselves in distant organs, and has discovered a transient phase during which these metastatic seeds are particularly vulnerable.
The researchers have also shown, both in mice and in human samples of brain metastases, that these micrometastases can be eliminated using three drugs, two of them already approved for other indications.
The study is published today in Cancer Cell . It is the result of research that began more than six years ago and was led by Manuel Valiente, head of CNIO’s Brain Metastasis Group. More than 70 co-authors from around 20 institutions in Spain, the United Kingdom, Germany, France and the United States took part.
Beyond identifying a previously unknown stage in metastatic development, the study has potential clinical implications. According to the authors, it opens up possible strategies to prevent metastasis from recurring after surgical removal, while also pointing towards one of oncology’s long-standing goals: tackling metastasis at such an early stage that it has not yet caused symptoms, which would effectively amount to preventing it.
At present, however, this is not yet possible, because there are no diagnostic tests capable of detecting micrometastases, nor are there biomarkers that can reliably identify patients at risk. But the discovery of a stage at which metastatic seeds are vulnerable “opens a window of opportunity to attack the disease before symptoms appear,” says Valiente. “This is the beginning of the race to prevent metastasis.”
The study, published today in Cancer Cell , states: “These findings reveal the existence of a previously unknown adaptive stage during metastatic colonisation and identify exploitable vulnerabilities to prevent brain metastasis progression and relapse.”
A ‘proliferative pause’ in which micrometastases are vulnerable
It was already known that cancer cells that colonise another organ — the brain, for example — must adapt to an environment that is very different from that of the tumour in which they originated, such as a tumour in the lung, breast or skin. This new environment is so hostile that many metastatic cells die during the adaptation process.
What this new research has discovered is that tumour cells that do survive enter a period the authors call a proliferative pause. During this stage, metastatic cells seek ways to survive in the new environment and temporarily abandon their aggressive behaviour.
The study focused on brain metastasis, although the authors hypothesise — and intend to investigate in future studies — that the vulnerable stage they have identified may be common to the metastatic process more broadly.
Molecular targets of drugs that are already approved
The study describes the molecular mechanism underlying this period of relative inactivity, as well as a way of blocking it so that cells in an incipient metastasis are unable to adapt to the new environment and therefore die.
“When we analysed the biology of these micrometastases, which are still clinically undetectable, we identified the molecular mechanisms that were active,” explains Manuel Valiente. “Because there are already drugs whose targets are precisely those molecules, we tested three of them in animal models. They worked: they eliminated the micrometastases before they could develop into detectable metastases.”
In addition to the experimental work in mice, Valiente’s group validated the findings using human tissue from two major research consortia.
Autopsy samples were essential
One of these was the UK-based PEACE consortium, a repository of tumour samples obtained from patients after death. This proved particularly valuable because autopsies are the only way to identify micrometastases.
“Thanks to PEACE, we were able to study metastases that had gone undetected in patients because they were too small. This is valuable in itself, because for the first time we have been able to assess the molecular profile of human micrometastases as they colonise the brain,” says Valiente.
After validating in patient samples the molecular mechanisms discovered in mice, the CNIO group began testing treatments in living human samples through the Spanish RENACER consortium, the National Brain Metastasis Network, founded by Manuel Valiente in 2021. RENACER is based on patients donating metastatic tissue removed during neurosurgery, meaning that these samples come from fully developed metastases.
Chief Investigator of the PEACE study, Mariam Jamal-Hanjani (UCL Cancer Institute), said: "Cancer spread to the brain can have devastating consequences for patients, and we know very little about the biology of this process in its earliest stages.
"This study has the potential to transform our ability to intervene with targeted drugs to prevent the progression of microscopic cancer in the brain and as a result improve outcomes and quality of life in patients. It also beautifully demonstrates how we can learn from patient samples in PEACE to translate research into viable future treatment opportunities”, added Jamal-Hanjani.
Clinical relevance for preventing relapse after surgery
At a later stage of the research, the team also showed that the molecular processes occurring during the vulnerable phase of micrometastases resemble those found at the leading edge, or invasive front, of established metastases — specifically in metastatic cells that spread by attaching themselves to the walls of blood vessels surrounding the metastasis.
This means that the study may also have implications for preventing relapse following surgery.
“Our previous research (Zhu et al., EMBO Molecular Medicine ) suggested that the cellular mechanisms involved in initiating metastasis are also active at the invasive fronts of established metastases,” explains Valiente.
This has now been confirmed. “We can halt the invasive fronts of human metastases using the drugs that are effective against the proliferative pause,” says Valiente. He adds: “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.”
Clinical trials in the medium term
The CNIO group’s medium- to long-term objective is to launch clinical trials to assess the effectiveness of the drugs tested in preventing brain metastasis.
For now, the researchers are focusing on the preparatory work needed to determine which combination of the drugs used produces the greatest therapeutic benefit.
Valiente’s group is also working on the identification of biomarkers that could detect micrometastases, which cannot currently be identified using existing techniques.
“The combination of biomarkers and drugs that are effective against micrometastases aims to prevent their progression to the stage at which they have clinical consequences for the patient.”
A broad collaborative effort
This complex study was made possible by national and international collaborations involving multiple institutions.
The National Centre for Genomic Analysis (CNAG), in Barcelona, carried out in situ single-cell analyses of patient samples.
The Center for Cancer Research at the US National Cancer Institute (NCI), in Bethesda, and UT Southwestern Medical Center, in Dallas, contributed new models of metastatic brain disease representing the most common primary tumours.
The Technical University of Dresden, in Germany, conducted studies to map multiple proteins in tissue samples.
The Instituto de Neurociencias, CSIC-UMH, in Alicante, contributed video-microscopy analyses of brain metastasis-initiating cells.
The University of Cantabria contributed electron microscopy analyses.
The Francis Crick Institute and University College London, in the United Kingdom, through the PEACE consortium, enabled the identification and characterisation of human brain micrometastases.
The University of Oxford, in the United Kingdom, and the University of Castilla-La Mancha contributed mathematical modelling of brain metastasis evolution.
The RENACER consortium enabled therapeutic strategies to be assessed in human brain metastasis samples.
Finally, multiple CNIO units, the CNIO Biobank and CNIO’s Brain Metastasis Laboratory contributed to and coordinated the study.
Cancer Cell
Experimental study
Human tissue samples
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28-Sep-2026