Study identifies genes that act as natural brakes on triple-negative breast cancer spread

Researchers uncover biological mechanisms that help prevent triple-negative breast cancer from spreading and show that restoring their activity reduced metastasis in preclinical models.

In a recent study, researchers from the Research Institute of the McGill University Health Centre (The Institute) identified four genes that regulate tumour progression and suppress metastasis in preclinical models of triple-negative breast cancer (TNBC). The researchers also uncovered the distinct biological mechanisms through which each gene limits cancer spread. These findings, recently published in the journal Nature Communications, could open new avenues for developing therapies designed not only to shrink tumours, but also to prevent cancer from spreading to other parts of the body.

“Preventing cancer dissemination is an important goal in cancer research, since most cancer deaths, including more than 90 per cent of deaths from breast cancer, are caused not by the original tumour, but by metastasis,” says Prof. Jean-Jacques Lebrun, PhD, senior author of the study and Senior Scientist in the Cancer Research Program at The Institute. “While much research has focused on identifying genes that promote metastasis, few studies have systematically searched for natural ‘brakes’ that prevent it.”

Using genomic approaches and CRISPR-Cas9 technology, the researchers found that the genes VPS45, RBSN, CMTR2, and NF2 helped limit the formation of metastases in multiple TNBC mice models, including models with both intact and compromised immune systems.
 

“When these genes were disabled, cancer cells became much more invasive, entered the bloodstream more readily, formed abnormal blood vessels and produced significantly more lung metastases, says Prof. Lebrun, also Professor of Medicine at McGill University. “Conversely, when we restored their activity, metastatic spread was dramatically reduced.”

Importantly, the study showed that CMTR2 helps regulate the organization of blood vessels within tumours and limits the ability of cancer cells to enter the bloodstream, a key step in the metastatic process. According to the researchers, these functions of CMTR2 had not previously been linked to breast cancer metastasis.

“Observing that tumours lacking CMTR2 developed highly abnormal blood vessels was a particularly exciting moment,” says Soaad Galal, first author of the study and PhD candidate in the Lebrun lab at The Institute. “Further experiments confirmed that this gene plays an unexpected role in controlling tumour angiogenesis—the process by which tumours develop their own blood supply to support their growth and spread—and in preventing cancer cells from escaping into the bloodstream.” 

By analyzing breast cancer patient datasets, the researchers found that the expression of these genes was reduced, particularly in patients with TNBC, which may help explain the aggressive metastatic behaviour of these tumours. They also found that lower expression was associated with more advanced disease, while patients with higher expression of these genes generally had better outcomes.

A study years in the making

This project began with a simple but ambitious question: Which genes normally stop cancer from spreading? To answer it, the team of researchers individually “turned off” nearly every gene in the human genome using patient-derived breast cancer cells.

The modified cancer cells were then introduced into mice, allowing the researchers to observe which cells were able to spread and establish metastases in the lungs.

By sequencing the resulting metastatic tumours, they identified exactly which genes, when disabled, had allowed cancer cells to spread, revealing genes that normally act as natural barriers to metastasis.

 “Rather than studying one gene at a time, we evaluated almost every gene in the genome directly in living mice, allowing us to see how tumours behave in a complex biological environment,” explains Prof. Lebrun.

The initial screen identified several candidate genes, and the team spent the following years validating the most promising ones using multiple breast cancer models, advanced imaging and molecular biology techniques, as well as analyses of patient tumour datasets.

Next, Prof. Lebrun’s team hopes to understand in greater detail how these newly discovered metastasis suppressor genes work at the molecular level and how their protective activity is lost during cancer progression.

“We also want to investigate whether these genes can be therapeutically reactivated,” says Prof. Lebrun. “Because restoring their expression significantly reduced metastasis in preclinical models, one exciting possibility is to develop treatments that switch these natural protective pathways back on. Ultimately, our long-term objective is to translate these discoveries into new strategies capable of preventing metastatic disease before it becomes life-threatening.” 

About the study

The study In vivo CRISPR screening identifies metastasis suppressors in triple-negative breast cancer, conducted by Soaad Galal, Leslie Chaltel Lima, Ni Wang, Cléo Moury, Gang Yan, Meiou Dai, Suhad Ali and Jean-Jacques Lebrun, was published in Nature Communications.

DOI: https://doi.org/10.1038/s41467-026-76293-x

The study was funded by the Canadian Institutes of Health Research (CIHR). Soaad Galal is the recipient of a Cancer Research Society (CRS) Scholarship Award.