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Cancer Cells Aren’t Purposefully Wasting Glucose, They’re Consuming It Too Quickly

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A new study by researchers at Washington University in St. Louis School of Medicine has shed light on why cancer cells consume excessive amounts of glucose, but do not always metabolize it efficiently. The research is published in Molecular Cell.

Glucose-craving cancer cells

Cancer cells require energy via glucose consumption to power their proliferation. So much glucose is consumed by cancer cells that one cancer diagnostic approach – positron emission tomography (PET) – involves using imaging to scour the body for regions of excess glucose consumption. 

What’s interesting, however, is that cancer cells do not use this excess glucose efficiently – much of it is released as waste material. This aspect of cancer metabolism has puzzled scientists for many years. “It is puzzling because tumors are rapidly growing, which requires a lot of fuel. It’s an incredibly interesting phenomenon that is named after the person who discovered it over a century ago – Otto Warburg [...] The biochemical logic for why cancer cells adopt such a seemingly unusual metabolic program has been somewhat elusive. An important step forward to advance our understanding of cancer is to characterize these apparent metabolic peculiarities, which will hopefully yield new therapeutic insights,” says Dr. Gary Patti, the Michael and Tana Powell professor of Chemistry in Arts and Sciences at Washington University in St. Louis School of Medicine.

Patti and colleagues have published a new study that adopts a metabolomics-based approach to shed some light on this query. “We can now measure the levels of thousands of metabolites from cancer cells in a single experiment. This allows us not only to monitor glucose, but also all the possible product molecules into which it can be transformed. Overall, metabolomics can provide a fairly comprehensive picture of what is happening inside cancer cells,” Patti explains.

What is metabolomics?

Metabolomics involves studying the entire metabolic profile of a cell, tissue or organism. Owing to advances in high-precision analytical technologies – such as nuclear magnetic resonance (NMR) and mass spectrometry (MS) – metabolomics has gained traction in the molecular biology research space over recent years.

Cancer cells become “glucose saturated”

The research team utilized metabolomics techniques alongside isotope tracers to overcome a current drawback of using metabolomics-based methods in isolation. “One current limitation of metabolomics is that it doesn’t directly report on where metabolites are within cells,” Patti explains. This limitation is important, as cells comprise smaller compartments – organelles – that each possess different functions within the cell. “To address this challenge in the present study, we took advantage of a clever and innovative approach developed by other researchers. It allowed us to infer where metabolites are within cells by using special labels that ‘tag’ molecules in specific subcellular locations,” Patti adds.

These methods were applied in cancer cell lines that have been studied extensively by the National Cancer Institute and other researchers. Each of these cell lines consume glucose, but the efficiency by which they use it varies. “We saw this as an opportunity to try to understand why some cancer cells are more wasteful with glucose than others,” says Patti. Ultimately, they discovered that cancer cells metabolize glucose – until they can’t. There is a variable capacity across cancer cell lines for using glucose efficiently. “When the route for using glucose efficiently becomes saturated at its maximum value, the cells become more wasteful,” Patti explains. An analogy for this process is an overflowing bathtub – once the water has filled the tub to its capacity, it begins to overflow over the sides of the bathtub, wasting water. “When we restrict the amount of glucose taken up by cancer cells, almost all of it makes its way into mitochondria,” Patti says. “But as glucose consumption is increased, the speed of moving glucose-derived molecules into mitochondria can’t keep up.”

He adds, “This is not a radically new metabolic paradigm. Most cells do prefer to oxidize glucose in mitochondria rather than excrete it as waste […] Our data suggest that cancer cells are not an exception. They appear to follow the same biochemical patterns as other cells.”

Targeting glucose metabolism may not be the most attractive approach for cancer treatment

What implications does this new finding on cancer metabolism have for current cancer diagnostic and treatment efforts? Patti and team propose that their data warrants a “rethinking” of how we best target glucose metabolism in cancer. “The best therapeutic targets are those that are specific to the disease cells. The classic example is the antibiotic penicillin. Penicillin targets the cell wall of bacteria, which human cells do not have. If glucose metabolism in tumors is indeed analogous to healthy cells, then it makes it more challenging to go after without also potentially disrupting normal tissue functions,” Patti says. Previously, scientists have proposed that limiting glucose uptake – either via pharmacological means or by reducing sugar consumption in the diet – could “starve” cancer cells. The new study suggests that glucose metabolism as a therapeutic target for cancer treatment may not be as attractive as once thought.

To further develop their research, Patti and colleagues are seeking to understand why some cancer cells have different capacities for glucose use than others. “It might have to do with the environment where the tumor is located, for example the lung versus the brain or liver. It will also be important to understand why cancer cells consume more glucose than they can use efficiently. Does the ‘extra’ glucose support the proliferation of cancer cells in some way, or is it functionally inconsequential?” Patti says. “The answers to these questions may reveal new targets for therapy.”

Many different cancer cell lines were explored in this study, but not all cancer types. “It will be important to continue to expand the analysis to broaden the scope and include additional cancers,” Patti concludes.

Professor Gary Patti was speaking to Molly Campbell, Senior Science Writer for Technology Networks.

Reference: Wang Y, Stancliffe E, Fowle-Grider R et al. Saturation of the mitochondrial NADH shuttles drives aerobic glycolysis in proliferating cells. Mol. Cell. 2022. doi: 10.1016/j.molcel.2022.07.007.