According to scientists at the Medical University of South Carolina, vaccinia-related kinase 1 (VRK1) over-expression, which had previously been though to cause cancer cells to migrate and invade, actually had the opposite effect. Their research was published in PLOS earlier this month.
Study director Paula Traktman, Ph.D., and graduate student Aye M. Mon started with the idea that high levels of VRK1 might be associated with breast cancer because other research had suggested this, and Traktman's own work had revealed that depleting VRK1 caused cells to grow more slowly and to cause smaller tumors and fewer metastases in mice. Drawing on these results, Mon and Traktman wanted to see how cells would grow when VRK1 was over-expressed. "The logic was that, if we over-express VRK1, maybe the cells would grow faster and maybe they would be invasive and migratory and contribute to metastasis," said Traktman.
To their surprise, they found that the opposite was true. When they over-expressed VRK1 in mammary epithelial cells growing in tissue culture dishes, those cells did not grow more rapidly than cells with normal levels of VRK1. And, contrary to their hypothesis, the cells tended to migrate and invade much more slowly. But, when the VRK1 over-expressors were cultured under 3D conditions that mimic tissues, they grew more rapidly and established larger colonies. Intrigued, Mon and Traktman took a closer look at the characteristics of these cells. They examined a hallmark of cancer cells known as epithelial-to-mesenchymal transition, or EMT. Many cells undergo EMT on their way to becoming cancer cells. The transition enables them to migrate away from the tumor.
They observed that the cells with high levels of VRK1 were more apt to form cell-to-cell connections and had lower levels of mesenchymal markers that are often present in cancer cells. Rather, the cells seemed to undergo the opposite transition, from mesenchymal to epithelial. The cells were much less likely to migrate.
These results pointed the researchers in a new direction. If high levels of VRK1 caused cancer cells to migrate more slowly, perhaps VRK1 was necessary to enable cells to colonize a new area of the body. In such a process, cancer cells spreading throughout the body would need to abandon the characteristics that make them spread and adopt the traits of cells that would anchor them in place. It is that kind of behavior that allows metastases to begin growing in other parts of the body.
To confirm their new hypothesis, Traktman and Mon teamed up with pathologist A. C. McKinnon at the Medical College of Wisconsin. McKinnon provided the team with cells from breast cancer patients who had metastases to their lymph nodes. They found much higher levels of VRK1 in the lymph node metastases than in the primary tumor cells. In addition, they examined the expression levels of VRK1 in public databases of breast cancer and found that high levels of VRK1 were associated with the most aggressive cancers.
Image: When mammary epithelial cells are grown in a 3D culture matrix, they proliferate and form hollow colonies that mimic the organization of an epithelial tissue. 3D cultures of control cells (left) and cells that over-express VRK1 (right) behave very differently in this context. Although all cells organize into colonies and form cell:cell junction markers (red, cadherin), VRK1 over-expression leads to much more vigorous cell proliferation and the formation of larger colonies. These results may have relevance to the colonization of tissues during cancer metastases. Image created by Paula Traktman from images appearing in Figure 5C of the September 4, 2018 article by Mon, MacKinnon and Traktman.