Risk and Reward

The Damon Runyon Cancer Foundation supports young scientists with creative, groundbreaking ideas leading to the prevention, diagnosis and treatment of cancer. Unlike many larger organizations, it funds research in its earliest stages.

USC Dornsife’s Matthew Pratt had one such idea. Pratt uncovered a possible connection between metabolism and protein modification in the human body, which contributes to the growth and survival of cancer cells.

Named a 2012 Damon Runyon-Rachleff Innovator, the assistant professor of chemistry and biological sciences is now able to pursue his research with a potentially huge payoff.

“The foundation takes a chance on young researchers like myself who are willing to try something new, and gives us funding so we can obtain preliminary data,” Pratt said.

Selected from more than 170 researchers nationwide, Pratt is one of five early-career scientists to receive the three-year grant. Pratt’s hypothesis stems from his research on the posttranslational modification of proteins, one of the final steps in the creation of proteins in the human body. His lab focuses on understanding how this chemical modification affects the function and expands the diversity of proteins, which participate in nearly all operations in a cell.

Immunofluorescent image of untreated A549 cells.

Pratt examined one type of modification — the molecule monosaccharide N-acetyl-glucosamine, known as O-GlcNAc. This modification is overexpressed in cancer cells, but the reason is not completely clear, Pratt said.

“We’re interested in why this modification is higher in cancer cells, and what the modification might be doing to promote cancer cell proliferation and survival,” he said. “What we do know is that if you can prevent the modification from occurring in cancer cells, they are no longer able to form tumors.”

Metabolism could play a large part in linking this modification to cancer cells.

Normal cells in adult humans metabolize glucose to create the energy the cells need to perform their necessary functions. The rate of metabolism in human cancer cells is much higher and more closely resembles the metabolism of our cells during fetal development. Instead of using glucose to make energy, cancer cells create copies of themselves, forming tumors. However, forming tumors causes oxidative stress in cancer cells, which they need to overcome to survive.

Pratt said that the O-GlcNAc modification, which is sensitive to changes in a cell’s metabolism, reduces the stress in cancer cells. He hypothesized that when glucose levels rise during the increased metabolism of cancer cells, so do the levels of the O-GlcNAc modification, which in turn lowers the stress levels and promotes the cancer cells’ growth.

Pratt and four USC Dornsife graduate students are investigating the details of this connection between O-GlcNAc modification and cancer cells. They are in the process of identifying which proteins are modified by O-GlcNAc.

Pratt and Leslie Bateman, a Ph.D. student in the Department of Chemistry in USC Dornsife, work in the lab. Photo by Ben Pack.

To examine the protein modifications, the group is using bioorthogonal chemistry — chemical reactions within living systems that allow researchers to examine interactions without interfering with the system.

“We want to be able to use chemistry to look at this modification in the presence of everything else that occurs in biology,” Pratt said.

Examining these elements at the molecular level may further the understanding of how metabolism promotes cancer and yield new opportunities for treatment.

“Our next step is to figure out where the modification occurs on key proteins,” he said, “and then to prevent it from occurring.”