Acidosis, the buildup of acidic metabolic byproducts, could alleviate the effects of other environmental stresses in pancreatic tumor cells, aiding the cancer’s survival.
When life gives cancer lemons, it says “thank you.”
Scientists recently discovered that in pancreatic tumors, acidic conditions made cells more resistant to other types of stressors, such as nutrient deprivation.1 Their results, published in Science, provide new insights into how tumor cells rise above harsh conditions and may guide researchers’ efforts in overcoming cancer’s resilience.
“It changes the way we think about tumor metabolism,” said Wilhelm Palm, a cancer biologist at the German Cancer Research Center and a coauthor of the study, in a statement. “Acidosis is not just a byproduct of altered metabolism in tumors. It’s a dominant factor that shapes energy metabolism in cancer cells and makes them resilient to different types of stress.”
Cancer cells go through a lot just to survive. Tumors are often poorly oxygenated and low in nutrients, so cancer cells often rewire their metabolism to thrive in these conditions. One of these adaptations, the Warburg effect, drives cells to metabolize glucose via glycolysis, which causes lactic acid to accumulate. The buildup of acidic byproducts from metabolism, called acidosis, can in turn produce more stress for cancer cells.
Many researchers who study how cancer cells withstand stress typically investigate these stressors independently. But in the body, tumor cells often encounter different types of stress simultaneously.
Aiming to understand this complexity better, Palm collaborated with Johannes Zuber, a cancer geneticist at the Research Institute of Molecular Pathology. First, the researchers wanted to identify the genes that help cancer cells withstand common types of stress in tumors—called fitness genes. They performed a genome-wide CRISPR-Cas9 knockout screen in pancreatic cancer cells and discovered hundreds of fitness genes.
To validate their findings in vivo, the researchers repeated the screen in a xenograft mouse model. Results from the in vivo screen revealed that under stress, the tumor cells shifted their metabolism to depend more on mitochondrial oxidative respiration than cytoplasmic glycolysis.
By comparing their in vitro and in vivo models, the team discovered that the addition of lactic acid to cells in culture recapitulated the effects that various stresses had on tumors. This suggested that acidosis is likely a key stressor that can reshape cancer cell metabolism.
To test this hypothesis, the researchers exposed pancreatic cancer cells to acidosis, alone or in combination with another stressor, such as glucose deprivation. Subjecting cells to both acidosis and glucose deprivation abolished the latter’s effects, indicating that acidosis could indeed make tumor cells more resilient to other stressors. On the other hand, when the team paired glucose deprivation with hypoxia, they observed an additive effect due to both stressors.
“This discovery is highly relevant for our search for more effective cancer therapies,” said Zuber. “With [this] knowledge, we can now search for therapies under these more realistic conditions and explore new ways to break this resilience.”
