Long thought to suppress cancer by slowing cellular metabolism, the protein complex AMPK has confounded researchers by seeming to help some tumors grow. In a study published today in Cell Metabolism, researchers have solved this long-standing mystery.
The researchers showed that late-stage cancers can trigger AMPK's cellular recycling signal to cannibalize pieces of the cell, supplying large lung tumors with the nutrients they need to grow. The work suggests that blocking AMPK in some conditions could stop the growth of advanced tumors in the most common type of lung cancer.
"Our study shows that the same dysfunction in a genetic circuit that causes non-small-cell lung cancer to begin with is necessary for more mature tumor cells to survive when they don't have enough nutrients," says senior author Reuben Shaw of the Salk Institute. "It's exciting because not only does it solve a genetic 'whodunnit,' but it also points to a potential new therapeutic target for a cancer that is often diagnosed very late."
AMPK acts as a fuel gauge for the cell, slowing down cell growth and changing the cell's metabolism when its fuel is low. In previous work, Shaw’s team discovered that AMPK could halt tumors' revved-up metabolism as well as restore normal function to the liver and other tissues in diabetics. But the Shaw lab's new work suggests that AMPK actually helps large tumors grow.
"We found that tumors grew much more slowly when AMPK was not present," says Lillian Eichner, the paper's first author. "That means that AMPK is not always functioning as a tumor suppressor as we originally thought."
The team analyzed which genes in tumor cells from the same mouse models were activated under various conditions. One gene that was particularly active was Tfe3, which is known to activate cellular recycling. It turned out that when the tumors became so large that the cells in the middle no longer had easy access to nutrients, AMPK signaled Tfe3 to initiate the recycling of cellular materials as nutrients for the tumor to use—effectively cannibalizing pieces of the cell.
"Previously, we were focused on how we could activate AMPK," says Eichner. "Now that we've identified this mechanism, we can shift to how to inhibit it in certain cancers."
Image: The solid purple indicates genetically engineered lung tumors within the native lung environment. Image courtesy of the Salk Institute.