A new study, led by researchers at the University of Chicago, provides an answer to why cancer cells consume and use nutrients differently than their healthy counterparts and how that difference contributes to their survival and growth.
A new study, published in the October 23 issue of Nature, shows that lactate, an end product of metabolism, changes the function of an immune cell known as a macrophage, thereby rewiring it to behave differently. This study, led by researchers at the University of Chicago, provides an answer to why cancer cells consume and use nutrients differently than their healthy counterparts and how that difference contributes to their survival and growth.
Almost 90 years ago, German physiologist and physician Otto Warburg first posed the question about why some cells consume nutrients differently. He knew that normal cells use oxygen to turn food into energy through a process called oxidative phosphorylation. But when he observed cancer cells, he saw that they preferred to fuel their growth through glycolysis, a process that involves consuming and breaking down glucose for energy. The phenomenon was coined “the Warburg effect.”
Lactate, the end-product of the Warburg effect, has long been considered a metabolic waste product. More recent studies showed that lactate can regulate the functions of many cell types, such as immune cells and stem cells. Thus, lactate is not simply a waste product, but may be a key regulator of cell functions in Warburg-associated diseases. Because the Warburg effect occurs in virtually all cancers, unraveling its mechanisms presents a rare opportunity to develop new targeted therapies that could have broad implications for many types of cancer.
Yingming Zhao, PhD, professor in the Ben May Department for Cancer Research at the University of Chicago and the lead author of the study, and Lev Becker, PhD, an associate professor at UChicago, used a laboratory technique called mass spectrometry to analyze the mechanisms driving the Warburg effect. They noticed that lactate, a compound generated during this process, also plays a non-metabolic role. Lactate is the source and stimulator of a new type of histone modification, which they termed histone lactylation.
Histone lactylation alters the structural units of DNA to change in cells the combination of genes expressed and functions of macrophages, (white blood cells) from a pro-inflammatory and anti-bacterial state (known as M1) to an anti-inflammatory and reparative state (known as M2), which plays an important role in infections and cancer.
Although this reparative M2 macrophage phenotype may help control damage during infection, its presence in tumors is known to promote growth, metastasis and immune suppression in cancer. These findings suggest that high lactate and histone lactylation levels in macrophages may contribute to the formation of tumors and their progression.
In addition to cancer, the Warburg effect is also observed in other diseases, including sepsis, autoimmune diseases, atherosclerosis, diabetes and aging. More research is needed on the role and regulation of this new histone modification, but the discovery draws an exciting link between cellular metabolism and gene regulation that was previously unknown and could have promising implications for human health.