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Accurate model of aggressive brain cancer developed

A brief chat at a Faculty Senate meeting put two University of Delaware researchers onto an idea that could be of great value to cancer researchers.

The collaboration of Prof. Prasad Dhurjati, a chemical engineer who has done extensive computer modeling of biological and engineering systems, and Prof. Deni Galileo, a neurobiologist whose expertise is in cell motion and behavior in the brain, has produced a new and freely available computer program that predicts cancer cell motion and spread with high accuracy.

An article on their model was recently published in BMC Systems Biology.

A significant challenge for physicians and their patients is that this cancer spreads rapidly, reducing the effectiveness of surgery, chemotherapy and radiation.

"You need at least 50,000 cells in one spot to pick it up in an MRI, so surgeons can't see where small numbers of cells have invaded the brain beyond the main tumor," Galileo said. "If you could stop the cells from moving beyond that initial tumor, the surgeon could go in a second time and take the second tumor out. As it is now, they can keep spreading in every direction and it's a pretty hard problem to solve."

Galileo and his research team have been studying what triggers the rapid spread of these cells - aiming to disrupt their aggressive advance - and have demonstrated the significant role of a cell membrane protein called L1CAM (L1 cell adhesion molecule).

Ordinarily, this molecule contributes to development of the nervous system, Galileo said.

But it acts differently in glioblastoma and other cancer cells, accelerating their growth and spread.

Dhurjati and Galileo met at a meeting of the Faculty Senate, which both have served as president.

Dhurjati looked at Galileo's work and realized it was a strong candidate for the kind of mathematical modeling he does with biological systems.

He has worked with specialists in osteoporosis and the human gut microbiome - that stew of microbes that live in the bellies of humans and animals - and has helped researchers simulate biological behavior to see predicted responses to various stimuli.

Galileo wasn't an easy sell, all involved agree.

Biologists, in general, don't have an easy relationship with mathematics, he said, and mathematics is central to computer models.

But Dhurjati persuaded him to give it a go, and undergraduate chemical engineering major and Honors degree candidate Justin Caccavale worked with Galileo to add the biological rules to the mathematical model.

"Biological details put me to sleep," Dhurjati said with a grin. "Mathematical equations put some biologists to sleep. But we all have something to contribute.... I've been a missionary to bring modeling into the world where people don't use models."

Together, with the help of undergraduate and graduate-level students, they constructed a computer model of Glioblastoma cells that accurately reflects what Galileo sees live cells doing under a microscope.

And that opens new opportunities for researchers.

"When your model represents real systems, you can play with the model in ways you cannot play with a human brain," Dhurjati said.

The simulation gives researchers new ways to ask many different questions: What if we disrupted this growth or motility signal? What if we added a chemotherapy drug here? How would those changes play out?

"But he has convinced me that modelling has good value in understanding how cells make decisions to be highly motile or proliferative," Galileo said. "This really does simulate why they move the way they do in a dish. They follow a simple set of rules.

"Biologists need to use more math and more modelling than what they do." Galileo said. "If the only models that come out are scary because of all the equations, they're never going to do that. If it's not too hard to modify for their purposes, there's a much greater chance they are going to adopt modeling as Prasad convinced me to do."

This model can be adapted to help researchers looking at other kinds of cells and is ideal for education purposes as biologists look for tools to enhance and strengthen their research capabilities.

Galileo's research focuses on cell behaviour in the brain. For his research on glioblastoma tumours, he uses brain cancer stem cells removed from patients during surgery through the Helen Graham Cancer Center and Research Institute at Christiana Care.

The cells are injected into chicken embryos, where they grow from tumours, spread and reveal their genetic mechanisms.

In normal brain cells, the protein he has studied in this research - L1CAM - is produced and used in healthy ways, promoting growth and development. But in these cancer cells, some of the L1CAM is exaggerated and cut off from the cell membrane.

Fragments of L1 then attach to the same cell or to nearby cells, triggering new signals among those cells and resulting in much more aggressive multiplication and spread of the cancer cells.

They have shown that restraint of the L1 protein reduces both the speed and the rate of cell division.

The computer model uses freely available software called NetLogo, which in this case takes biological rules and integrates them with glioblastoma cell data gathered in Galileo's lab.

The program looks at each cell as a separate agent and accounts for random or stochastic behaviours that biological systems often exhibit.

It does not account for every conceivable biological possibility, however, and is - at this two-dimensional stage - a fairly simple representation. There are plans to advance to a three-dimensional model using NetLogo 3D.

"We are not interested in stopping cells in a dish, but in a brain," Galileo said. "The next step is to go into a somewhat three-dimensional brain slice model and ultimately we want to model the total three-dimensional behaviour of how cells move around. But we have to start simply and that's how we'll progress this model."

As the research advances, the models will improve accordingly.

Source: University of Delaware

 

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Founding partners

European Cancer Organisation European Institute of Oncology

Founding Charities

Foundazione Umberto Veronesi Fondazione IEO Swiss Bridge

Published by

ecancer Global Foundation