University researchers reveal key protein structure for cancer spread

Sunday, April 24, 2016 - 7:01pm

A University of Michigan research team led by John Tesmer, professor of pharmacology and biological chemistry, published a study earlier this month on a structure of a protein that might be important for preventing the spread of cancer throughout the body.

Metastasis is the spread of the primary cancer from its original location to other parts of the body. Metastasis can occur when the cancer cells invade other tissues by dividing or traveling through the lymphatic and the circulatory systems to other parts of the body.

Metastatic cancer — cancer that has gone through metastasis — is diagnosed as stage IV cancer and is the most dangerous for patients. People who are diagnosed with stage IV cancer have much lower survival rates than those who are diagnosed with early-stage cancer. For example, 52 percent of people diagnosed with early-stage lung cancer live for at least five years after the diagnosis, but only four percent of people diagnosed with stage IV cancer do.

Tesmer’s team focused on a protein called P-Rex1 — a protein that allows cells to become mobile. Jennifer Cash, a research fellow in Tesmer’s group and the lead author of the study, said she and the rest of the team studied P-Rex1 because of its association with metastasis.

“It has been shown that P-Rex1 is significantly produced in prostate cancer, breast cancer and melanoma,” Cash said. “When cancer cells start making (P-Rex1), it allows the tumor cells to become mobile and metastasize to other parts of the body.

Cash added that, in spite of how fatal metastatic cancer is for patients, metastasis is still poorly understood, and this is why most cancer drugs are designed to combat tumor growth, not metastasis.

“Metastasis is a significant problem,” Cash said. “Most cancer mortality occurs from metastases, not from primary tumors.  Despite this fact, most cancer drugs target tumor growth, not metastasis. Historically, this is mostly because of a lag in our understanding of how metastasis works.”

The team used a tool called X-ray crystallography, which is used to identify the molecular structure of proteins through light diffraction. Cash said knowing the structure of P-Rex1 is important in figuring out its role in the cells because a protein’s function is largely based on its structure.

“The job that a particular protein carries out is related to its shape,” Cash said. “We can use (X-ray crystallography) to get snapshots of a protein that help us to figure how that protein works.”

Cash said that, because P-Rex1 makes cells mobile, a potential way to fight metastasis is to design drugs with certain shapes that allow them to interact with P-Rex1, but interfere with the protein’s function, which allow the cells to move to different parts of the body. Cash used an analogy with keys and keyholes to illustrate this idea.

“You can imagine that P-Rex1 has two keyholes on its surface and there are two other molecules … that fit into these keyholes to turn on the protein,” Cash said. “We’re trying to figure out the shape of the keyholes, the shape of the keys and how those interact to turn on the protein. If we know what the keyhole looks like, we can begin to design keys that would fit into the keyhole, but not be able to turn on the protein.”

One of the next steps for Cash and rest of the team is to find which “keys” fit into the “keyhole” of P-Rex1 and turn on the protein, as well as how those keys that interact with P-Rex1. This would allow them to design strutures in the future which could inhibit this process, preventing metastasis.

Cash emphasized that more studies are needed to achieve a more complete picture of how P-Rex1 is regulated in the cells and how P-Rex1 can be used to fight metastasis.

“Collectively, the regulation of P-Rex1 is very, very complex,” Cash said. “We’ve really just scratched the surface at this point, but we’re on our way toward addressing our next questions on P-Rex1 regulation.”