Tracking a Killer

ENG prof tries to determine what makes cancer cells migrate, invade

| From Research Magazine | By Chris Berdik

Quantitative visualizations like this model of a tumor’s extracellular matrix offer a better understanding of how tumor metastasis functions in children and adults. Image courtesy of Muhammad Zaman

Muhammad Zaman’s fight against brain cancer in kids began with a wrong turn. A few years ago, while searching for a colleague’s lab in the University of Texas’s M.D. Anderson Cancer Center, he got lost and ended up in the pediatric ward.

“My daughter had recently been born, and it pained me to see how many of these kids were probably not going to make it,” says Zaman, a College of Engineering assistant professor of biomedical engineering.

Zaman had been seeking a clinical application for his research into the physical, chemical, and biological details of cancer cell migration in the body, what’s known as metastasis. Partnering with researchers at the Massachusetts Institute of Technology and the University of Manchester (UK), he decided to focus on pediatric brain cancer, which gets much less research attention than the most common childhood cancer, leukemia. Zaman’s goal is to use his intricate computational and experimental models of pediatric brain cancer cell migration to pinpoint the key biochemical mechanisms that support metastasis.

Traditionally, he says, clinicians followed a “Mini-Me strategy” when it came to treating cancer in kids, simply cutting the dose of the same chemotherapy drugs used for adults. But children’s rapid development means that the environment in which cancer grows and migrates in their bodies is far different than it is in adults.

In addition, one of the major reasons why so many chemotherapy drugs fail when transitioning from the lab to the clinic, Zaman says, is that they are developed by watching cancer cells move on two-dimensional plastic surfaces. The key for more successful drug development, therefore, is to study cancer cell migration and test therapeutics using a more lifelike model of a biological system.

“It’s not about looking at a single gene in isolation. It’s about how genes and the environment interact, how one protein influences another, and how those interact with the cellular systems and with the structures inside the body,” says Muhammad Zaman.

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Supported by nearly $2 million in funding from the National Institutes of Health, Zaman and his research partners use a laser-scanning microscope to track cultured cancer cells moving through three-dimensional “matrices” of a common protein such as collagen, or a synthetic soft-tissue. They then assemble the time-lapse microscopic images into detailed computer simulations of real-time cell movement.

“This is what the cells see as they travel through the matrix,” says Zaman, as he plays one such video on his computer; it shows a tunneling journey through the amorphous network of a porous protein structure. The experiments are used in combination with computational models Zaman has built from what is already known about cell signaling and cell binding, and about the stresses and the forces operating within the matrix. He periodically refines and improves the models based on experimental data.

“We’re trying to find out what enables or hinders cancer cell migration and invasion, so that people will be able to develop therapeutics that specifically target those mechanisms,” says Dewi Harjanto, a biomedical engineering doctoral student who works with Zaman.

While most studies look at individual cancer cell migration, Harjanto is investigating how clusters of cancer cells, mini-tumors, sometimes migrate away from the main tumor. She is focusing on how the density of the collagen matrix affects this movement.

Another collaborator, Roger Kamm, an MIT professor of mechanical and biological engineering, is using microfluidic systems to see how cancer cell movement is affected by varying the fluid flow through the matrix. Other experiments alter the pH of the matrix or the DNA of the cancer cell. Eventually, says Zaman, they will introduce different drugs to these systems, “to see what happens to those cells and their ability to move, divide, and form tumors.”

No matter what variable is being altered, “this is a systems question,” Zaman stresses. “It is not about looking at a single gene in isolation,” he says. “Instead, it’s about how multiple proteins inside the cell interact with the environment of the tumor, how one protein influences another, and how those interact with the cellular systems and with the structures inside the body.”

This article originally appeared in Boston University’s Research Magazine 2010.

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