A new study published today in Science has shown for the first time how an acidic pH in the tissue surrounding pancreatic cancer cells triggers changes in their mitochondria that contribute to faster tumor growth, metastasis, and treatment resistance.
As a solid tumor develops, its environment can increasingly become more acidic in a process known as acidosis. While previous studies had drawn a link between acidosis and tumor aggressiveness in pancreatic cancer, it was not understood how exactly acidosis contributes to a poorer prognosis, or whether acidosis was rather just a symptom of other underlying processes.
With pancreatic cancer being one of the most lethal forms of the disease, understanding drivers of tumor growth and aggressiveness is essential to identify more effective treatments. Now, researchers have figured out the cascade of events that lead pancreatic cancer cells to rely on an acidic environment to switch their metabolism and become more aggressive.
“Our results show that acidosis is not simply a by-product of tumor metabolism, but an important switch that controls the energy supply and survival strategies of cancer cells,” said Johannes Zuber, MD, senior group leader at the Research Institute of Molecular Pathology (IMP) in Vienna and senior author of the study.
Zuber and colleagues set out to study how pancreatic cancer cells adapt to the hostile conditions of the tumor microenvironment, which include lower levels of oxygen, glucose and key nutrients in addition to acidosis. Using CRISPR-Cas9 as a screening tool, the team identified hundreds of genes that play an important role in the survival and growth of the cancer cells under these stress conditions. The effects of these genes were then studied in knockout mouse models of pancreatic cancer.
Results showed that the survival and growth of cancer cells was determined by changes in their metabolism that allowed them to adapt to acidosis. In fact, the acidic environment triggered a switch in pancreatic cancer cells from glucose-based energy production to mitochondrial respiration, allowing them to use energy more efficiently to fuel their growth.
“It is not just the lack of oxygen or nutrients that changes the metabolism in the tumor—it is primarily the acidification of the tumor environment,” said Wilhelm Palm, PhD, head of the division of cell signaling and metabolism at the German Cancer Research Center (DKFZ) in Heidelberg.
Normally, the mitochondria are small and fragmented in cancer cells. However, acidosis was found to inhibit the ERK signaling pathway that drives this fragmentation process. This resulted in mitochondria merging with each other to form extensive networks that could produce energy more efficiently from a variety of nutrients.
Based on these results, the researchers believe that therapeutic interventions that address acidosis or prevent mitochondria from fusing could destabilize the metabolism of cancer cells to slow down their growth under acidosis. While pancreatic cancer is particularly susceptible to acidosis due to the importance of pH in this organ, which produces the alkaline pancreatic juice, this strategy could potentially be expanded to other solid tumors where acidosis is detected.
