Energy waves on cancer cell surfaces linked to tumor growth and aggressiveness

In a bid to better understand how cancer cells power their explosive growth and spread, scientists at Johns Hopkins Medicine say they have shed new light on the location and function of power-generating waves on the covering, or membrane, of these cells. The scientists say the waves, generated by rhythmic propagation of enzymes that produce energy from glucose, could potentially be used to better stage cancers, and as targets of drugs designed to slow down or halt the spread of cancer.

In experiments with human cancer cells grown in the laboratory, the researchers also suggest that measuring the energy-producing waves could help to stage cancers in a more universal and standardized way, regardless of subtypes and genetic mutations.

A report of the findings, funded in part by the National Institutes of Health, was published July 1 in the journal Nature Communications. 

Our findings suggest a correlation between higher levels of the energy-producing waves and a greater severity of the cancer, or the cancer's potential to spread to other organs."

Peter Devreotes, Ph.D., the Isaac Morris and Lucille Elizabeth Hay Professor of Cell Biology at the Johns Hopkins University School of Medicine

In cancer biology, scientists have long known of the Warburg effect, a process in which cancer cells utilize more energy from a less efficient pathway - glycolysis - rather than the more efficient mechanism, oxidative phosphorylation.

"That appears to be a paradox for cancer because cancer cells need much more energy to grow than normal cells," says David Zhan, Ph.D., postdoctoral researcher in Devreotes' lab. 

The researchers say it was taught in biochemistry class for many decades that glycolysis occurred uniformly in the cytosol, or the fluid matrix of the cell. 

But when the Johns Hopkins team examined cancer cells grown in the lab, they found that energy-generating enzymes gather and move as waves on the cell membrane, suggesting a more fine-tuned energy production process.

"This finding may challenge the canonical textbook knowledge that we all learn from the biochemistry course," Zhan says.

Zhan and colleagues began the study by comparing samples of normal cells from the lining of human breast ducts with the same type of cells from people with breast cancer. The scientists used genetic engineering to tag fluorescent molecules to these glycolytic enzymes, enabling visibility and accurate measurement of these energy-producing enzymes under a high-powered microscope.

In breast cancer cells, the scientists found an abundant amount of glycolytic enzymes on the cells' membrane, and that the molecules moved in organized waves. In normal cells, the scientists observed almost no glycolytic enzymes in the cell surface or waves.

"The more aggressive the cancer, the more waves we found on the cell surface," says Devreotes. This discovery stems from earlier research from Zhan and Devreotes, published in 2020 in Developmental Cell, which suggests that cancer stages are linked to glycolytic wave activity.

In the most recent study, the scientists measured the level of ATP, the energy "currency" within breast cancer and normal cells, and found that more aggressive breast cancer subtypes were associated with higher levels of ATP produced from these waves.

Using other cancer cell types, including lab-grown cell lines of human pancreatic, lung, breast, colon and liver cancers, the researchers found similar results: increases in wave activity and levels of ATP in subtypes of cancer considered to be more aggressive when compared with less aggressive types of cancer cells.

"The increased presence of these glycolytic waves drives more ATP production from glycolysis in cancer cells, and that leads to enhanced reliance on glycolysis for energy," Zhan says.

In search of a way to slow down the cancer cell energy wave activity, they used a small molecule, Latrunculin A (LatA), that disrupts the assembly of the glycolytic waves in cancer cell lines. The scientists then found a 25% decrease in ATP, suggesting that cancer cells largely depend on these waves to fuel and execute their daily energy-intensive activities.

"When we inhibit the activity of these waves, we may be able to stop these cancer cells from being able to consume nutrients and grow," says Zhan. "Cancer cells require a lot of energy to drive cancer malignancy, so disrupting this process might be able to slow or stop its spread."

Next, Devreotes says his team plans to investigate exactly how the energy-producing waves occur in the cell membrane.

Funding support for this research was provided by the National Institutes of Health (GM118177, FA95501610052, R01GM136711, S10 OD016374), the Multidisciplinary Research Program of the University Research Initiative of the Air Force Research Laboratory, the Defense Advanced Research Projects Agency, a Cervical Cancer SPORE Pilot Project Award (P50CA098252), the Sol Goldman Pancreatic Cancer Research Center, a Johns Hopkins Discovery Award and the W.W. Smith Charitable Trust Award.

In addition to Devreotes and Zhan, other scientists who contributed to this work are Dhiman Sankar Pal, Jane Borleis, Yu Deng, Yu Long and additional corresponding authors Chris Janetopoulos and Chuan-Hsiang Huang of Johns Hopkins.