VARI Uncovers Vitally Important Clue

April 6, 2007
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GRAND RAPIDS — Scientists at the Van Andel Research Institute have zeroed in on a clue as to how cancer cells spread from their site of origin to other parts of the body.  

VARI Senior Scientific Investigator Art Alberts, Ph.D., and his research team in the institute’s Laboratory of Cell Structure & Signal Integration discovered that a naturally occurring cellular protein known as DIP can activate cell bubbling, or “blebbing,” which has recently been identified as a possible mechanism in cancer cell metastasis.

VARI researchers found that DIP binds to and inhibits the activity of the protein mDia2, a protein that works to keep tumor cells from migrating. When DIP binds to mDia2, it causes the affected cells to change shape and bubble, or bleb. It appears cell blebbing, in turn, inhibits the control mDia2 has over tumor cell matastasis, so it may contribute to the development of secondary tumors, which more cancer patients die from. Eisenmann said scientists have only recently identified cell blebbing as an important physiological process, and they’re just beginning to understand its underlying biochemistry. One idea, she said, is that cancer cells bleb as they invade normal tissue.

Before now, scientists were aware of the existence of DIP but unaware of its ability as an inhibitor. Alberts said several labs, including his own, had previously identified DIP as a binding partner for a variety of different proteins. 

In other words, in cells n cells,

Cells use different kinds of modes to move, and all have the ability to move to some degree. The interaction VARI discovered between mDia2 and DIP, plus the fact that DIP is an inhibitor of mDia2, suggests that the whole interaction is essentially a molecular switch between the modes of cell movement, Alberts explained. Next, they’ll look at how that interaction is regulated.

“Knowing that DIP plays a role in inhibiting mDia2 and triggering blebbing gives us insight into the fundamental mechanism that control cancer cell movement,” Alberts said. “By identifying the role of DIP-Formin protein interaction, we now have a mechanism that we can target with drugs aimed at interfering with cancer metastasis. This is vitally important because, currently, no anti-cancer therapies block this critical step in the malignancy process.”

Certain drugs might be used to manipulate DIP and prohibit it from binding to the mDia2 protein or they might be used to incapacitate DIP completely.

“In some cases we might want to make this switch happen and in some cases we may want to block it,” Alberts said. “The key reason why it’s important and why we’re excited about the interaction is the fact that it actually happens; we know there is an affect on the cell shape when this happens. It gives us a handle on a mechanism that we can look at and explore different ways of modulating it.” 

Alberts believes the study is fundamentally important because mDia2 is a member of the Formin family, a group of proteins that are found throughout biology, and DIP is the first-to-be discovered natural inhibitor of Formin protein activity. His team believes the observed interaction is going to have relevance to people studying different types of organisms in other mechanisms, because more often than not those mechanisms tend to replicate themselves throughout biology.

Researchers used video time-lapse microscopy to observe the blebbing process. Eisenmann said scientists only recently identified cell blebbing as an important physiological process, and they’re just beginning to understand its underlying biochemistry. One idea, she said, is that cancer cells bleb as they invade normal tissue.

“When we introduced DIP into cervical, T-cell leukemia and breast cancer cells, we found it drastically altered cell structure and shape and ultimately caused the cells to bubble, said Kathryn Eisenmann, Ph.D., lead author of the study. “Our findings would likely have implications for multiple types of cancer.”

Cancer and maybe even other types of disease, because there are a lot of diseases that stem from defects in cell structure, and the ability of cells to interact, communicate and move, Alberts added.

The study appears in this month’s issue of Current Biology, a peer reviewed scientific journal. Two researchers from the DartmouthMedicalSchool in New Hampshire collaborated with VARI scientists on the study. The American Cancer Society, the National Institutes of Health and the Van Andel Foundation funded the study.     

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