Scientists discover an “impossible” cellular survival pathway that could help fight cancer
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A molecular geneticist at Montana State University has uncovered a previously unknown survival mechanism that allows mammalian cells to produce the amino acid cysteine even when the cellular systems normally responsible for supplying it stop working. Scientists once thought this kind of survival was impossible.
The finding, published in Nature Chemical Biology, could eventually point researchers toward new ways to make some cancers more vulnerable to treatment.
“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.”
Why Cells Depend on Cysteine
Cysteine performs several essential jobs inside cells. It is used to make proteins, helps cells protect themselves from damage and contributes to the formation of disulfide bonds. These bonds help stabilize proteins and maintain their three dimensional structures.
For decades, researchers believed that cells could not simply obtain cysteine from their surroundings. Instead, they must generate it internally by breaking apart cystine, an oxidized form of cysteine.
Cells normally accomplish this through what is known as a disulfide reductase system. Scientists had long assumed that having at least one functioning version of this system was essential for cellular life.
“Scientists long believed this process was absolutely essential for all living cells,” Schmidt said. “However, we have discovered a previously unknown system in mammalian cells that can take over when the main systems fail.”
Mice Survived When They Should Not Have
The discovery unfolded in three stages over nine years.
Schmidt said the first major clue appeared in 2014, when a colony of genetically engineered mice survived under conditions that, according to scientific understanding at the time, should have been fatal. The mice lacked any known mechanism for converting cystine into the cysteine their cells required.
“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.”
The finding was not the result of an accidental observation. Schmidt had previously engineered mice whose liver cells separately lacked one or the other of the two main disulfide reductases.
The behavior of those animals made him question whether the prevailing assumption about cell survival was correct.
“Some of the physiological responses we were seeing in the livers of each of those mouse lines suggested to me that the belief that no cell could live without having at least one of these two reductases might not be correct,” he said. “I wanted to test this.”
A Hidden Backup Pathway
Finding the explanation took another seven years.
Schmidt’s team worked with collaborator Peter Nagy and his group at the Hungarian National Institute of Oncology in Budapest. Nagy’s team contributed analytical capabilities that helped the researchers determine how the cells were still obtaining cysteine from cystine despite lacking a working disulfide reductase system.
They found that mammalian cells possess an alternative chemical route.
When the usual disulfide reductase pathway is unavailable, this backup mechanism breaks an adjacent carbon sulfur bond within cystine. That reaction ultimately frees cysteine that the cell can use.
The pathway provides cells with another way to obtain a molecule that is essential for survival, even after their better known machinery has failed.
An Ancient Defense Against Toxins
Schmidt said this backup system may originally have evolved as a defense against electrophilic toxins.
Many such toxins are organic molecules produced by organisms as chemical weapons against predators or competing organisms. By giving cells another way to survive chemical stress, the newly identified pathway may have provided an evolutionary advantage to early multicellular organisms.
“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.
A Possible Weakness in Cancer Cells
The same mechanism that protects healthy cells could also have a less helpful consequence.
Researchers suspect that some cancer cells may use this backup pathway to survive chemotherapy, radiation therapy or immune therapy. Those treatments are designed to damage or destroy cancer cells, but cellular defense systems can sometimes help tumors endure the stress.
“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.”
If scientists can learn how to selectively interfere with the pathway in tumors, the discovery could eventually provide another way to increase the effectiveness of existing cancer treatments.
Students Helped Drive the Discovery
Several Montana State University students contributed to the research, including some who have since graduated.
Zoe Seaford and Sydney Austad served as co-first authors and conducted their work as undergraduate students in Schmidt’s laboratory. Martina Serrano Alvarez and Reed Noyd also participated while they were undergraduates, and Colin Miller contributed as a doctoral student.
Scientists and trainees from several other institutions also collaborated on portions of the work.
“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.”
Schmidt joined Montana State University in 1999. His research spans gene regulation, cell and organismal physiology, mouse genetics, embryology, biochemistry, metabolism and laboratory mice whose DNA have been genetically altered by inserting one or more genes from another organism into the mouse genome.
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