Like all living things, cancer, too, must eat to survive. Yet some tumors, such as those in the pancreas, manage to thrive even in environments where nutrients are scarce. A new study by researchers at NYU Langone Health, published in the journal Nature, describes for the first time how this mysterious survival technique works and, critically, how it might be sabotaged to treat or even cure pancreatic cancer.
Pancreatic ductal adenocarcinoma is rare but deadly, killing most patients within two years of diagnosis. New treatment strategies are badly needed. “To address this high unmet need for patients, we really need to think about entirely new ways of targeting these types of cancer,” says first author Craig Ramirez, PhD, who spearheaded the research as a graduate student and postdoctoral fellow in the laboratory of Dafna Bar-Sagi, PhD, executive vice president, vice dean for science, and chief scientific officer at NYU Langone.
In the 1980s, Dr. Bar-Sagi discovered that a protein called RAS can kick-start a scavenging mechanism that allows cancer cells to engulf nutrients from their immediate surroundings to survive during lean times. This seminal finding helped explain, in part, why mutations in RAS have been linked to 95 percent of pancreatic cancers and nearly one-third of all cancers. Until now, though, little has been understood about the cellular chain reactions that make it all work.
“To learn more about what exactly controls this scavenging mechanism, we began with a large screen that identified a few potential regulators,” explains Dr. Bar-Sagi. “From there, the lab did a lot of painstaking detective work to knock out the candidates one by one, ask how their absence affected the process, and start connecting the dots.”
The end result is a kind of map that shows how multiple interconnected proteins in cancer cells with certain RAS mutations work together to drive the scavenging process and thrive under harsh conditions.
The lab focused on two proteins in particular: SLC4A7 and vacuolar ATPase. Both are required for the intricate series of steps that lead a cell’s membrane to bulge out and form a pocket to engulf nearby nutrients, fueling tumorous growth. In pancreatic cancer cells, the researchers saw increased levels of the SLC4A7 protein and more vacuolar ATPase congregating in the right location for the scavenging to occur.
“We are now searching for drug candidates that might inhibit the action of these two proteins as potential future treatments that block the scavenging mechanism,” says Dr. Bar-Sagi. “Both are in principle good targets because they’re linked to cancer growth and operate near the cancer cell surfaces, where a drug delivered through the bloodstream could reach them.”