Montana State researcher discovers a critical cellular system that may one day lead to treatment of some cancers

BOZEMAN - A molecular geneticist at Montana State University has discovered a cellular process once believed impossible by scientists and which may one day lead to new cancer treatments.

The findings were published May 21 in the scientific journal Nature Chemical Biology, which is available online.

"All cells need a constant supply of an amino acid called cysteine in order to stay alive," said the paper's lead author Ed Schmidt, a professor of genetics and development in the Department of Microbiology and Cell Biology in MSU's College of Agriculture. "Yet cysteine is not available outside of the cells."

Cysteine is critical to cells because it helps them build proteins and defend against damage. It also enables the formation of disulfide bonds, which stabilize proteins to help cells keep their three-dimensional shape.

Researchers have known for decades that cells have no external source of cysteine, so they must create it themselves by chemically splitting an oxidized form of it - called cystine. This chemical process driven by the cellular disulfide reductase systems.

"Scientists long believed this process was absolutely essential for all living cells," said Schmidt, who has been with MSU since 1999. "However, we have discovered a previously unknown system in mammalian cells that can take over when the main systems fail."

This discovery was made in three stages over a nine-year period. The first "aha moment," Schmidt said, came in 2014, when researchers observed a colony of mice convert cystine into cysteine even though they had no known way to do so.

"This was supposed to be impossible," he said. "No living organism or cell had ever been found that could live without having a functioning disulfide reductase system."

Schmidt and his team, in partnership with Peter Nagy and other researchers at the Hungarian National Institute of Oncology in Budapest, worked for seven years to uncover how the mice were making cysteine. What they learned was that when cells cannot use a disulfide reductase system, a backup system chemically steps in, severing an adjacent carbon-sulfur bond in the cystine, ultimately releasing cysteine for the cell to use.

This newly discovered backup system, which is common to all mammals, Schmidt said, might help humans survive by protecting cells from what are known as electrophilic toxins - molecules that some organisms make to kill other organisms that would otherwise eat them.

"The ability of our cells to survive, at least for a time, without disulfide reductases, likely evolved in our earliest multicellular ancestors as a mechanism that allowed these organisms to resist being killed by electrophilic toxins made by the things they ate or the things found in their environment," Schmidt said.

Notably, this backup system might also help some cancer cells survive exposure to chemotherapies, radiation therapies or immune therapies.

"This same pathway that protects our cells from oxidants or toxins also likely protects cancer cells from therapies," Schmidt said. "Now that we know they have this defense mechanism, we might be able to precisely disable it in cancers, making them more susceptible to cancer therapies, as well."

Several MSU students, some of whom have since graduated, coauthored the paper, including Zoe Seaford and Sydney Austad, who did their work as undergraduate students in Schmidt's lab and shared lead-author honors. Martina Serrano Alvarez and Reed Noyd were also undergraduate students in the lab when they participated in the project, and Colin Miller was a doctoral student. Other scientists and trainees from various institutions also collaborated on portions of the research presented in the paper.

"This scientific breakthrough underscores the power of research to redefine what we thought was possible and advance new approaches to cancer treatment," said Sreekala Bajwa, dean of the agricultural college. "I congratulate Dr. Schmidt and his team for their exceptional achievement and for engaging students as true partners in research that delivers global impact."