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Modeling for New Research
By Emily Carlson
Posted September 24, 2008

Biomedical researchers develop computational and mathematical models for many reasons, like predicting how a biological system behaves or exploring questions nearly impossible to answer in the lab. Cancer biologist Alissa Weaver uses models to generate new research hypotheses—and results.

Weaver's latest work stemming from a modeling project offers up new details that could explain why women with denser breast tissue typically have more aggressive tumors.

Two years ago, Weaver led part of the Vanderbilt Integrative Cancer Biology Center (VICBC) hands-on workshop, an annual program that brings together mathematicians, computational scientists, and biologists to work on a current question in cancer. During her session, Weaver and participants brainstormed new models of cancer and how it spreads.

Breast cancer cell with active fingerlike protrusions called invadopodia (pink) that degrade the extracellular matrix (green). Credit: Kevin Branch of the Weaver Lab

At the time, Weaver was relatively new to the world of computational biology. Trained as a medical scientist, she focused her research on understanding the movement of cancer cells and the mechanisms that allow them to invade different tissues.

When the National Cancer Institute launched VICBC in 2004 to develop models for studying cancer, Weaver naturally got involved. "A lot of people are now becoming interested in applying models to make sense of disease,” she says. "They're a tool that can help us think about a problem differently or lead to an experiment that we might not do otherwise.”

The brainstorming session inspired Weaver and her lab to develop a simple model that simulated how fingerlike protrusions on cancer cells penetrate the three-dimensional matrix surrounding them. By poking holes in the matrix, the protrusions allowed cancer cells to move through tissue. The model and experiments to validate it both suggested that another element might be involved: the density of that extracellular matrix.

Numerous studies had already linked invasive forms of breast cancer to denser breast tissue. Did the density of the extracellular matrix alter the ability of the fingerlike protrusions to drill through to surrounding tissue, enabling cancer to spread? Weaver suspected "yes.”

To find out for sure, Weaver ran some experiments using breast cancer cells on a substrate that mimicked the extracellular matrix. Since the matrix acts as a barrier to cell movement, you'd think that a denser matrix would be even more impenetrable. Weaver's group found the opposite: Increasing the density actually increased the ability of the cells' protrusions to break through the matrix.

"But just because you know what's involved,” says Weaver, "doesn't mean you know how it works.”

To better understand this unexpected phenomenon, Weaver's team looked for other changes that occurred when they increased density. It turns out that denser substrates were also more rigid. Cells can sense physical forces, such as those exerted by a stiffer matrix, and can convert them to chemical signals needed for cellular operations. In this case, the chemical signals promoted the formation and activity of the protrusions.

The next step, Weaver says, is to study these complex interactions in more detail. Future experiments not only will increase our understanding of cancer invasion but improve our abilities to model it.