Liver cancer is one of the deadliest types of cancer – partly because it is often only discovered at a late stage. A study has now uncovered which changes in cell metabolism lead to healthy liver cells becoming cancerous. The molecule acetyl-CoA, which is involved in numerous metabolic processes, plays a key role here. It is downregulated in liver cancer, the researchers found. This returns cells to an undifferentiated state and allows them to multiply excessively. The new findings could help to identify metabolic markers for the early detection of liver cancer in the future.
The liver is the largest metabolic organ in our body. It processes and stores nutrients and breaks down pollutants. Various risk factors can contribute to liver cells degenerating and forming tumors. The most common causes include viral infections such as hepatitis C, metabolic disorders such as diabetes, and obesity and high alcohol consumption. In Germany, liver cancer is relatively rare with around 10,000 new cases per year, with men being affected more often than women. However, since the tumor is often only discovered at a late stage, liver cancer is one of the most common causes of cancer-related death.
Devastating changes
A team led by Sujin Park from the University of Basel has now investigated at the molecular level what happens when a previously healthy liver cell becomes cancerous. “Tumor cells are selfish. They change their metabolism in such a way that they grow as quickly as possible,” explains Park's colleague Dirk Mossmann. "At the same time, they neglect all their tasks as liver cells. This is why liver function is impaired in cancer patients.” For their study, the researchers examined samples from liver tumors from human patients on the one hand, and observed the processes taking place in mice with liver tumors on the other.
They discovered that a central molecule of cell metabolism is downregulated in liver tumors: acetyl-coenzyme A (acetyl-CoA). This molecule is an end product of many degradation pathways and is capable of making or chemically altering numerous other molecules by attaching a small chemical appendage called an acetyl group to them. As a result, it is involved, among other things, in cellular signal transmission and in the regulation of gene expression.
metabolism reprogrammed
"We found that all possible metabolic pathways that produce acetyl-CoA are shut down in liver cancer cells," explains Park. “This affects many other proteins such as metabolic enzymes. The function of the enzymes changes because they are no longer modified by acetyl-CoA. This can help the tumor cells to better break down sugar and to gain energy from it.” Another effect is that acetyl-CoA influences the differentiation of cells. Low acetyl-CoA levels reprogram liver cells and revert them to an early, immature stage of development. They lose their characteristic function and quickly begin to divide.
But how do tumor cells manage to paralyze all acetyl-CoA metabolic pathways? "The answer came from two proteins, so-called transcription factors," says Mossmann. "They control the reading of a wide range of genes and thus completely change the metabolism." In experiments with mice, the researchers demonstrated that two transcription factors called TEAD2 and E2A actually play a central role in the downregulation of acetyl-CoA and the development of liver cancer. "If we inhibited the two transcription factors, the mice no longer developed liver tumors," reports Park. Even if tumors were already present, switching off TEAD2 and E2A ensured that the acetyl-CoA concentration rose again and tumor growth was inhibited.
Biomarkers for early detection?
Unlike in mice, it is not possible in humans to simply switch off these two transcription factors, which also perform other important tasks in the body. However, the findings could possibly help to improve the early detection of liver cancer: "The extensive metabolic changes in the tumor cells result in a typical signature that can also be found in other types of cancer such as prostate and pancreatic cancer," says Park. The current study does not reveal exactly when this cancer signature develops. However, if it actually occurs in an early phase of the disease, even before the patient develops symptoms, it could serve as a biomarker for screening and thus make it possible to detect tumors at an early, treatable stage.
Source: Sujin Park (University of Basel) et al., Molecular Cell, doi: 10.1016/j.molcel.2022.10.027