Austrian Researchers Identify Metastasis-Suppressing Protein

Research findings out of the Institute of Science and Technology Austria (ISTA) could help explain one of oncology’s biggest mysteries: why some cancers metastasize and others do not. The team has identified a protein that plays a role in recycling receptors that help keep cells from migrating, and clinical data support the findings.   

The findings, published recently in Frontiers in Oncology, builds upon earlier work by ISTA that identified a protein in fruit flies that impacts cell migration. For the current study, they created mouse cancer cells lacking MFSD1, its mammalian counterpart. Without the protein, cells traveled much faster, suggesting that MFSD1 prevents cells from moving.  Together with collaborators from the University of Zurich, they then tested their theory in living mice with breast, colon, and skin cancer. In the absence of MFSD1, there was a strong increase in metastasis.

The researchers then performed a stress test on cancer cells with and without the protein. “We wanted to know why lower MFSD1 levels were beneficial to the tumor apart from allowing them to move more freely. As cancer cells travel through the blood for example, they experience a lot of mechanical stress,” says lead author Marko Roblek. The stress test involved trying to scrape the cells off the surface of the Petri dish in which they had been grown. While the cancer cells containing MFSD1 quickly died under the mechanical stress, those without the protein tended to remain intact.

Without the protein, the team concluded, certain tumor cells could more easily enter the bloodstream and find their way to other parts of the body.  In a subsequent experiment, the researcher tested the cancer cell’s resistance to nutrient starvation with a similar result. Again, the cells lacking MFSD1 survived for longer.

MFSD1 works by affecting specific receptors located at the cell surface. Called integrins, these receptors  ensure cells stick to each other and the extracellular matrix. In a constant circle, the cell produces these receptors, transports them to the cell surface and back inside the cell. If a tumor cell lacks MFSD1, they fail to recycle a certain type of integrin. “The result is, that the cells stick less to the surrounding tissue and each other, which makes it easier for them to migrate,” says coauthor Daria Siekhaus.

The team’s findings are also supported by an analysis of patient data by Rita Seeböck from the University Hospital St. Pölten, Austria. The data showed a correlation between the level of MFSD1 and the patient’s prognosis. “We’ve seen that patients suffering from specific forms of breast, gastric and lung cancer who had lower levels of MFSD1 had a worse outcome. A high level of MFSD1 seems to be protective—it works like a suppressor of tumor metastasis,” Roblek says.

The findings could impact diagnostics, treatment plans, and even lead to new gene therapies based on the gene encoding MFSD1. “If this marker becomes more established, doctors can use it to help classify how aggressive the cancer is and to decide between different treatment options,” Siekhaus says.

In future studies, the team wants to focus in detail on how the protein functions on a molecular level and discern if artificially raising the amount of MFSD1 could help suppress the spread of certain tumors. The long term goal is to examine if it can be used as a therapeutic target.