Atomic Fingerprint Analysis Reveals Cancer Cells

Scientists are still trying to understand the molecular details of how cancer cells metabolize and get energy; the details can open new, more precise ways to help identify cancer cells amongst normal ones. What they do know is that cancer cells get most of their energy via fermentation, a metabolic process that generates less energy but operates very fast.¹ This also helps them grow much faster than normal cells.

In a recent study, former Princeton University postdoctoral researcher Ashley Maloney, currently a biogeochemist at the University of Colorado Boulder, and her co-authors discovered that fermenting yeast cells, that grow fast and resemble cancer cells, have fewer heavy hydrogen isotopes called deuterium in their lipids.² In comparison, yeast cells that get their energy in a process called respiration—a slower but more energy yielding process—have more deuterium in their lipids. Reporting their findings in Proceedings of the National Academy of Sciences, the team also found this difference between healthy and cancerous mouse liver cells, with the latter having fewer deuterium in their lipids. Though the findings are yet to be tested in human cells, the team hopes that their study lays the foundation for an atomic fingerprint diagnostic tool to identify human cancers in the future.

As the daughter of a dermatologist, Maloney knew a lot about skin cancer even before she got into science. Amidst all of cancer’s mysteries, what specifically intrigued her was how cancer cells metabolized nutrients very differently as compared to normal cells. Working as a biogeochemist during her PhD at the University of Washington, she learned that algae use hydrogen isotopes while metabolizing different molecules in their cells.

She pondered about connecting her work to cancer cells.

“I always wondered how cancer metabolism versus healthy metabolism, [happening in] cells right next door, would change the hydrogen isotope composition of the lipids in those cells,” she said. In her postdoctoral work with Xinning Zhang, an environmental microbiologist at Princeton University, she was able to explore this question.

Lipids get their hydrogen from a molecule called nicotinamide adenine dinucleotide phosphate (NADPH) in the cell, which acts like a hydrogen carrier. In the process of making lipids, NADPH transfers its hydrogen atoms to lipid molecules. Multiple enzymes in the cell generate NADPH, and most of them prefer to use the lighter hydrogen atom. But one of them, called cytosolic isocitrate dehydrogenase (cIDH), has an equal preference for both the heavier and lighter hydrogen atom. As a result, when it acts, it generates a pool of NADPH with heavier hydrogen atoms, which are then passed onto the lipids. And this enzyme is more active during respiration and less during fermentation, the process preferred by fast-growing yeast and cancer cells.

Ashley and her team monitored fast-growing yeast colonies and cancerous mouse liver cells—that got their energy from fermentation—along with another type of slower growing yeast and healthy mouse liver cells that metabolized food via respiration. The scientists then isolated the lipids from the cells and ran them through a mass spectrometer, a tool that could help them get an idea of the kinds of hydrogen atoms present in the lipids.

They found large differences in the heavier to lighter hydrogen atom ratios, with fermenting fast-growing yeast cells showing much fewer deuterium atoms in their lipids as compared to the respiring yeast cells. Cancerous mouse liver cells also had fewer deuterium atoms in their lipids, but the difference was not as stark as in the yeast cells.

“So, lipids are giving us a hint of what's happening inside the cell, with the NADPH in particular, and that's why it's cool,” said Maloney. “They're telling us this story that's almost kept secret,” she added.

Zhang had previously seen variations in heavy and light hydrogen atom ratios in lipids in bacteria.³ But this is the first time scientists report seeing this in eukaryotic organisms, like yeast and mice cells, according to Wil Leavitt, an earth scientist at Dartmouth College. He hopes to see this technique tested with human cancer samples in the future.

“The yeast work is really beautiful,” said Leavitt. “[But] does this technique work in identifying cancer cells or biomarkers in a clinical setting? That'd be cool,” he added.