While the rapid spread of COVID-19 infections chews up the daily news cycle, other swiftly progressing and devastating diseases such as pancreatic cancer still ravage the population.

“Pancreatic cancer is predicted to soon become the second-leading cause of cancer-related deaths in the U.S.,” noted Cosimo Commisso, PhD, assistant professor at Sanford Burnham Prebys Cancer Center and senior investigator on a new study that may have uncovered a new method for killing pancreatic cancer cells. “Given that the five-year survival rate for people newly diagnosed is less than 10%, it’s crystal clear that we need better therapies—and finding new cancer targets can help us tailor treatments and possibly save the lives of many more patients.”

Commisso and his colleagues reported on how depleting an ion transport protein lower the pH to the point that compromises pancreatic cancer cell growth. The findings from this new study were published recently in Cancer Discovery through an article entitled “Golgi Acidification by NHE7 Regulates Cytosolic pH Homeostasis in Pancreatic Cancer Cells.”

Pancreatic cancer cells—like all cancer cells—have a constant need for energy to support their growth and expansion. To meet these energy needs, they boost metabolic pathways that normal cells don’t use and, consequently, produce excess acid that needs to be expelled. Increasingly, scientists have focused on manipulating cancer cell pH as an approach to treat cancers lacking effective therapies.

“Our study suggests that interfering with cellular pH represents a new therapeutic avenue to treat pancreatic cancer, one of the deadliest cancers for which there is currently no effective treatment,” Commisso, explained. “We have shown that a sodium-hydrogen exchanger called NHE7 plays a significant role in pancreatic tumors, and by suppressing it, we can promote cancer cell death.”

The NHE family of sodium-hydrogen exchangers are transport proteins that regulate the internal pH of cells and their organelles such as endosomes and the Golgi apparatus. They are located in membranes and work by exchanging hydrogen ions (H+) for sodium ions (Na+) and are essential for proper cell function.

“Cancer cells reprogram their metabolism to meet elevated energy demands and favor glycolysis for energy production,” the study authors wrote. “This boost in glycolytic flux supports proliferation, but also generates acid in the form of hydrogen ions that must be eliminated from the cytoplasm to maintain the alkaline intracellular pH (pHi) associated with transformation. To cope with acid production, tumor cells employ ion transport systems, including the family of sodium-hydrogen exchangers (NHEs).”

“We hypothesized that the increased acid production that occurs in tumor cells could be harnessed as a therapeutic vulnerability, so we looked for a strategy to specifically target this,” added lead study investigator Koen Galenkamp, PhD, a postdoctoral fellow in Commisso’s lab. “By mining a number of pancreatic cancer databases, we found that NHE7 levels were higher in tumors compared to the normal pancreas, and highest in the tumors of patients with the poorest prognoses.”

With this information, the research team set out to understand the role of NHE7 in pancreatic cancer cells. They found that it localizes to the Golgi, where it imports hydrogen ions, creating an acidic Golgi and a corresponding alkaline cytoplasm that supports cancer cell metabolism.

“We identified NHE7 as a novel regulator of pHi in pancreatic ductal adenocarcinoma (PDAC). We determine that NHE7 suppression causes alkalinization of the Golgi, leading to a build-up of cytosolic acid that diminishes tumor cell fitness mainly through the dysregulation of actin. Importantly, NHE7 knockdown in vivo leads to the abrogation of tumor growth.”

“This led us to test if we could make pancreatic cells vulnerable by disabling or eliminating NHE7 to undermine the alkaline cytoplasmic pH they require to stay fit,” Galenkamp remarked.

Through a series of experiments in pancreatic cancer cells, the research team showed that suppressing NHE7 lowers the pH of the cell’s cytoplasm, triggering cell death. Importantly, in mice transplanted with human tumors, getting rid of NHE7 caused tumors to shrink or completely stop their growth.

“This study illustrates the potential to target pH balance as an approach to combat pancreatic cancer,” Commisso concluded. “Our next step is to work with the Conrad Prebys Center for Chemical Genomics—the drug discovery facility at our Institute—to find ways to disable NHE7 and limit the Golgi’s ability to sequester acid. If successful, cancer cells would be unable to maintain the proper pH that they need to grow.”

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