▎WuXi AppTec content team editor
Pancreatic ductal adenocarcinoma (PDA) is a highly malignant type of tumour that most treatments do not help. This high lethality stems from its special tumor microenvironment, which is filled with large dilated fibroblasts as well as extracellular matrix deposits.
This means that the capillaries in PDA tumors collapse under pressure. Lack of functional blood vessels can lead to poor drug permeability, but the tumor itself does not receive adequate nutrition. According to our understanding of tumors in the past, fast-growing cancer cells naturally need a lot of energy, and glucose is the best raw material.
Image source: 123RF
For this reason, some studies have also tried to "starve" cancer cells by blocking their glucose metabolism. But for PAD, it's not okay to starve them by cutting off sugar. Due to the lack of blood vessels, their rapid growth has long been dependent not on glucose in the blood, but on a molecule called uridine.
In a recent paper published in Nature, the authors screened 19 PDA cell lines for the growth-promoting properties of more than 175 nutrients, including some sugars, proteins, and lipids of general interest, as well as many other molecules containing carbon or nitrogen.
Using the glucose group as a control, the researchers found several metabolites that were used by cancer cells at levels comparable to glucose, and most PDA cell lines chose adenosine, uridine, and several other sugars as energy sources. According to the metabolic activity assessment, uridine and glucose promoted metabolism to a similar degree in the four PDA cell lines.
In addition, not only uridine, uridine-derived ribose can also support the metabolism of cancer cells and promote the growth of PDA.
In addition to cell dishes in vitro, this set of metabolic processes in mice can also work. With the help of genetically engineered pancreatic cancer mice, the researchers periodically injected them with radiolabeled uridine, and as a result, within 1 hour, they detected large amounts of uridine in the tumor. These uridines are broken down and are involved in several key physiological metabolic processes such as nucleotide composition, glycolysis, and the tricarboxylic acid cycle of cancer cells.
▲Among the many nutrients, in addition to glucose, cancer cells have a high use of uridine (Image source: Reference [1])
Dr. Costas Lyssiotis, corresponding author of the study, noted that cancer cells develop so-called "crisis time" events when faced with competition or when blood vessels are not open, "they sense the concentration of glucose and uridine in the environment and act adaptively." "According to their tests, when glucose concentrations are high, the proportion of cancer cells using uridine is relatively low; Once glucose gradually disappears, the carbon in uridine occupies most of the metabolic cycle.
In uridine metabolism, uridine phosphorylase 1 (UPP1) is very important, UPP1 tends to cooperate with uridine metabolism to increase the expression level, and once the expression of UPP1 is blocked, the pancreatic tumor growth of mice will be significantly hindered, which also proposes a new "starvation" tumor method.
Similarly, a study in Nature Metabolism last week published a similar conclusion, according to the paper, when cancer cells are in sugar-free media, they only need to add some RNA to it, and they can break down the uridine in it for growth. In this experiment, the authors observed that uridine is most pronounced in glycolytic processes in melanoma, but also in other cancer types. This also shows that cancer cells' ability to break down and metabolize uridine is so common that we may have been underestimating their ability to obtain energy from molecules other than carbohydrates.
Resources:
[2] Study finds cancer cells use a new fuel in absence of sugar. Retrieved May 23, 2023 from https://medicalxpress.com/news/2023-05-cancer-cells-fuel-absence-sugar.html
[3] Cells can use uridine, a component of RNA, as a source of energy. Retrieved May 23, 2023 from https://medicalxpress.com/news/2023-05-cells-uridine-component-rna-source.html