Directing cancer cell migration
A team of researchers at Sanford-Burnham has discovered how a single protein directs cancer cells to move and spread from one part of the body to another. The study, published in the Journal of Biological Chemistry, shows that it is an intricate balance between levels of the full-length protein with levels of its cleaved segments that control a tumor cell’s ability to metastasize.
“We have discovered how protein-tyrosine pseudokinase 7 (PTK7) controls cell motility and metastasis,” said Alex Strongin, Ph.D., professor in the Bioinformatics and Structural Biology Program. “This is important because in cancer, metastasis is what kills. Understanding how PTK7 enables cancer cells to spread may lead to new approaches to controlling metastasis.”
Cell Polarity Prior to the study, researchers knew that PTK7 was essential for epithelial cell polarity. Polarity is a fundamental feature of epithelial cells that allows them to connect to one another and form sheets of cells that line the surfaces throughout the body, and maintain structural order. In epithelial-cell cancers—known as carcinomas—cells lose their polarity, bundle together to form tumors, and in some cases metastasize. About 80 to 90 percent of cancers are epithelial-cell cancers, and these include most lung, breast, prostate, and bowel cancers.
PTK7 PTK7 is a transmembrane protein, meaning that part of its structure is outside the cell (extracellular), part spans the cell membrane, and part resides inside the cell (intracellular). Prior to the study, scientists knew that when PTK7 is in its full-length configuration it has anti-metastatic effects. They also knew that in metastatic tumors, levels of PTK7 were elevated. Finally, they knew that PTK7 could be cleaved on the extracellular portion by a few enzymes, including one called membrane type-1 matrix and metalloproteinase (MT1-MMP), cutting the protein into segments.
So how do the pieces of the PTK7 puzzle fit together? By using a combination of animal models and human colon cancer specimens, the research team was able to show how a tightly controlled process of enzymatic cleavage of PTK7 regulates the dynamics of cell polarity, and is critical for directing epithelial cell motility, invasion, and metastasis. When PTK7 is full length, it stabilizes cell polarity. As the levels of MT1-MMP increase, more PTK7 is cleaved, and cells become free to move from one part of the body to another.
“We are looking forward to creating tools that can distinguish whole PTK7 from cleaved PTK7, because it appears that it’s the ratio of the two that may provide information on the likelihood that a carcinoma will spread,” said Strongin. “It’s also clear that blocking the enzymatic cleavage of PTK7 may be a way to prevent metastasis. But it will be important to find molecules that selectively inhibit MT1-MMP-PTK7 cleavage because the MT1-MMP enzymes perform many normal cell functions as well.”