Researchers at the University of Illinois Chicago have identified a molecular switch that helps determine whether cancer cells remain soft and difficult to destroy or become stiff enough for the immune system to attack.
The study, led by researchers in the College of Medicine and published in the journal Developmental Cell, sheds new light on how the physical properties of cancer cells influence metastasis — the spread of cancer — and points to a promising new therapeutic target.
"The physics of cancer are very counterintuitive. The outer shell of a tumor is very rigid: Even the patients can feel the hardness of a growing tumor lump," said Ekrem Emrah Er , assistant professor of physiology and biophysics and senior author of the study. "But the individual cells inside the tumor are very soft and flexible and gooey, which allows them to kind of leak out. Then they disseminate and metastasize to different organs.
"If a cell is soft, it's much harder for an immune cell to attack it and shatter it," said Er, a member of the University of Illinois Cancer Center. "Instead, the cancer cells bend, but they don't break."
Scientists have known for years that metastatic cancer cells tend to be softer and squishier than healthy cells, but the mechanisms behind this quality have remained unclear. Researchers have been searching for a practical drug target that could make cancer cells stiff and easier for the immune system to attack.
The UIC team found one in an ion channel protein called KCNMB1, which helps regulate the movement of potassium ions across cell membranes. Activating this pathway increases cell stiffness, making the cancerous cells more susceptible to attack by T cells and natural killer cells, two of the immune system's cancer-fighting weapons.
Cell softness isn't inherently a problem. Many of the body's cells soften when they travel through the body.
But when cancer cells get too soft, immune cells have a harder time defeating them. Rather than shattering them like a ceramic plate when they attack, they bounce off them like jelly.
The discovery builds on previous work from Er's laboratory showing that a protein called myocardial-related transcription factor A, or MRTFA, can increase cellular stiffness. But this protein, it turns out, is not an ideal target for drugs.
"It's not a great drug target, because it's a transcription factor. If you were to mess with something that high up in a pathway, you can cause a whole bunch of downstream effects that are unintentional," said Alexa Gajda , the paper's first author, a postdoctoral fellow and a recent doctoral graduate from UIC.
Instead, the researchers searched for genes that were activated alongside MRTFA. By comparing gene expression patterns and conducting follow-up experiments, they identified KCNMB1 as a key downstream player controlling cell stiffness. When the team reduced KCNMB1 expression, cancer cells became softer; when they enhanced its activity, cells became stiffer.
The finding is especially attractive because ion channels are already common pharmaceutical targets. Drugs that act on ion channels are routinely used to treat cardiovascular disease, stroke and other conditions.
"That was a convenient outcome," Gajda said. "There are already drugs that target these kinds of channels, which means there may be a clearer path toward translating these findings into therapies."
The researchers tested one such drug, a potassium-channel activator called BMS-204352. In animal models of metastatic breast cancer, the drug reduced distant tumor growth in the lungs and helped restore the ability of immune cells to kill cancer cells. The effect depended on functional T cells, suggesting that the treatment works in part by improving immune recognition of metastatic cells.
The study also found that tumors create potassium-rich environments that can soften cancer cells and suppress immune responses. Activating the potassium channel reversed those effects, restoring stiffness and improving immune-cell activity.
While additional research is needed before the approach can be tested in patients, the findings suggest a promising strategy for fighting metastasis.
"It gives us another front to fight against cancer — a biophysical front," said Er.
Written by Tess Joosse
