Why some cancer patients develop metastases and others do not is largely unclear. Researchers headed by Daria Siekhaus, PhD, at the Institute of Science and Technology (ISTA) in Austria, are now contributing to a better understanding of the process in certain types of cancer. Their studies have found that a solute carrier protein known as MFSD1 acts to prevent cancer cells from migrating, and so restrains metastatic spread.

The scientists’ experiments in tumor-bearing mice showed that loss of MFSD1 enabled higher levels of metastasis, while analysis of data from patients with different tumor types found that downregulation of MFSD1 expression occurs during early steps of tumorigenesis, and that higher MFSD1 expression levels correlated with better cancer patient prognosis.

Reporting on their results in Frontiers in Oncology, Siekhaus and colleagues acknowledged that while further work will be needed, their results suggested that “drugs capable of enhancing MFSD1 activity or its expression could thus potentially aid in inhibiting the progression of certain tumors.” The team described its findings in a paper titled, “The solute carrier MFSD1 decreases β1 integrin’s activation status and thus tumor metastasis.”

Solute carriers (SLCs) are the second most numerous class of integral membrane proteins, the authors wrote. Encoded by 456 known genes, SLCs are outnumbered only by G-protein coupled receptors. Solute carriers effectively transport a broad spectrum of different molecules, such as sugars, neurotransmitters, vitamins, nucleosides, and amino acids, and are essential for the maintenance of homeostasis in mammalian cells, tissues, and organs, the investigators continued. However, they stated, “About 100 SLC genes are known to cause Mendelian disorders upon mutation, while more are expected to have roles in multigenic diseases.” Currently, there are 19 SLC proteins targeted by drugs, and more than 30% of solute carriers remain orphan, such that their physiological substrates and functions aren’t known.

Daria Siekhaus, PhD. In a previous study, the Siekhaus group at ISTA found that the fruit fly version of MFSD1 affects cell migration. [© ISTA/Nadine Poncioni]

Siekhaus and colleagues took a close look at the role of an SLC protein called MFSD1 (major facilitator superfamily domain-containing protein 1), which is the mammalian relative of a protein they had previously identified as affecting cell migration in fruit flies. First author Marko Roblek, PhD, from the Siekhaus group, created mouse cancer cells lacking the MFSD1 protein. Experiments showed that without the protein, the cells traveled much faster, suggesting that MFSD1 acts to prevent cell movement. “MFSD1 restrained migration in the three tumor cell lines we tested,” the team noted. Together with collaborators from the University of Zurich, the ISTA team also tested their theory in live mice with breast, colon, and skin cancers. The results confirmed: “In the absence of MFSD1, there was a strong increase in metastasis,” Siekhaus noted.

 

First author Marko Roblek, PhD, helped identify a protein that suppresses tumor metastasis. [© ISTA]

“We wanted to know why lower MFSD1 levels were beneficial to the tumor apart from allowing them to move more freely,” Roblek added. “As cancer cells travel through the blood, for example, they experience a lot of mechanical stress.” So, to investigate the effects of stress, the researchers performed a stress test on cancer cells that expressed MFSD1, and on those that lacked the protein. Using a tiny rubber scraper, Roblek tried to scrape the cells off the surface of the Petri dish in which the cells had been grown.

While the cancer cells containing MFSD1 quickly died under 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 another experiment, the researcher tested the cancer cell’s resistance to nutrient starvation with a similar result. Again, the cells lacking MFSD1 survived for longer.

The team’s studies showed that both the cell’s reaction to starvation and mechanical stress are linked to MFSD1, and that this relates to how the protein affects specific integrin receptors located at the cell surface. Such integrins ensure that the cells stick to each other and the extracellular matrix. In a constant cycle, the cell produces the receptors, transports them to the cell surface and back inside the cell. So if a tumor cell lacked MFSD1, it failed to recycle a type of integrin known as β1 integrin. “The result is, that the cells stick less to the surrounding tissue and each other, which makes it easier for them to migrate,” said Siekhaus. As the authors concluded, “Here we identify a cell biological function regulated by MFSD1, namely the recycling of β1 integrin from the endolysosomal system utilizing a murine colon carcinoma cell line. We show that this capacity underlies MFSD1’s regulation of migration.”

The team’s findings were supported by the results of patient data analyses, carried out by Rita Seeböck, PhD, from the University Hospital St. Pölten, Austria. The data showed a correlation between MFSD1 levels and patient prognosis. The authors noted, “MFSD1 expression levels correlate with the survival of patients with lung, breast, and gastric tumors and down-regulation of MFSD1 expression happens during early events of colon tumorigenesis.”

Roblek commented, “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.”

As part of optimizing therapy for their patients, doctors are analyzing the expression of certain genes. The researchers suggest that looking for the gene encoding the protein MFSD1 may also be useful. “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,” suggested Siekhaus. The long-term goal is to examine if MFSD1 might represent a therapeutic target. “In future studies we also aim to unravel the molecular function of MFSD1, aiding the development of drugs potentially useful for therapeutic intervention,” the team concluded in their paper.