In young mouse livers, cells with a mutation that kept β-catenin continuously active disappeared; in chronically damaged livers, they formed tumors

In young mouse livers, cells with a mutation that kept β-catenin continuously active disappeared; in chronically damaged livers, they formed tumors

On August 10, Nature Communications published a study in which researchers introduced an activating β-catenin mutation into only about 1–3% of hepatocytes, the main cells of the liver, in male mice. They permanently labeled these rare cells to track their fate among their normal neighbors.

Mutations can remain in tissues for years without producing a tumor. This experiment tested how the condition of the liver affects the fate of rare cells carrying the same mutation.

β-catenin participates in growth signaling and helps cells maintain their specialized state. Activating changes in its gene are frequently found in hepatocellular carcinoma, the most common primary liver cancer. The authors therefore tracked the behavior of this mutation in individual hepatocytes surrounded by normal tissue.

In young, healthy livers, the number of labeled cells still matched the control after one month, although the cells themselves had grown larger. After two months, their number fell sharply and reached its lowest point by the third month. The cells accumulated reactive oxygen species, which are chemically aggressive molecules, and showed impaired function of the endoplasmic reticulum, the cellular system in which proteins acquire their functional form. Prolonged stress was accompanied by cell shrinkage and their gradual elimination.

In the chronic liver injury model, some of these cells had already formed expanding clones by the third month. After 6,5 months, visible tumors were present in every liver in this group. Clones also expanded in mice that received the mutation at 15 months, but they remained smaller.

The researchers found that a protective mechanism helped the expanding mutant cells survive oxidative stress. These cells activated the NRF2 program. NRF2 is a protein that turns on antioxidant defenses. Disabling the NRF2 gene slowed clone expansion and tumor development. In some animals, large tumors arose from cells in which the gene had not been successfully disabled. In young livers, clones expanded rapidly when the researchers activated a constitutively active form of NRF2 or AKT, a protein involved in transmitting growth and survival signals.

In these models, the β-catenin mutation initially triggered a stress response in the cells. In damaged and old livers, some cells activated protective mechanisms, survived, and proliferated. The condition of the tissue therefore changed the fate of cells carrying the same mutation before a tumor appeared.