Hyaluronic acid is a known presence in pancreatic tumors, but a new study published by Kim et al in eLife has shown that hyaluronic acid can also act as a nutrient to fuel pancreatic cancer metabolism. These findings provide insight into how pancreatic cancer cells grow and indicate new possibilities for the treatment of this malignancy.
“A central driving theme in my research lab is that pancreatic cancer doesn't respond to the common arsenal of treatment approaches. We need to think about this challenge differently,” said lead study investigator Costas Lyssiotis, PhD, of the University of Michigan Medical School. He and his team study the metabolism of pancreatic cancer in preclinical models: how cells obtain nutrients and the spectrum of nutrients they utilize to fuel growth and enable therapeutic resistance.
Costas Lyssiotis, PhD
The Tumor Microenvironment of Pancreatic Cancer
The tumor microenvironment is comprised of a combination of many different cell types—some malignant, some not. A pancreatic tumor’s microenvironment is highly stromal, meaning the mass itself is mostly comprised of connective tissue and non-cancerous immune cells.
“Stroma occurs in the body’s natural scarring process,” Dr. Lyssiotis explained. “As these scars are formed, an abundance of hyaluronic acid gets released.”
Hyaluronic acid—a polymer or long chain of sugars—attracts and retains water. When there is a high concentration of hyaluronic acid present, pancreatic tumors become hyperdense, collapsing veins and blood flow. Dr. Lyssiotis explained that these tumors become very hard.
“It’s not that there aren’t veins or arteries inside the tumor. But the vasculature that is there can’t withstand the extreme pressure.”
Most studies of hyaluronic acid in pancreatic cancer have focused on its role in creating this density; a recent unsuccessful clinical trial even explored ways to degrade hyaluronic acid and release pressure on the tumors to allow the vasculature to expand and deliver drugs, which are typically difficult to administer given the lack of blood flow.
Role of Hyaluronic Acid in the Current Study
Dr. Lyssiotis and his lab wanted to understand hyaluronic acid beyond its contribution to the physiological make-up of pancreatic cancer cells. They considered the density of these tumors, and wondered: If cancer cells aren’t getting access to blood-derived nutrients, how are they getting the nutrients that fuel cell growth and become tumors?
The lab’s new work indicates that one way cells do this is by scavenging the hyaluronic acid itself.
“Hyaluronic acid doesn’t only affect tumors by creating this density, which does make it difficult to treat,” Dr. Lyssiotis said. “It is literally a chain of sugars. In retrospect, it makes good sense that the malignant cells are also feeding off hyaluronic acid.”
Dr. Lyssiotis said this study demonstrates just how well pancreatic cancer cells scavenge nutrients in order to maintain their survival and growth. “We’ve added another example into a growing body of evidence of the nutrients and pathways we didn’t think cancer cells would use to scavenge.”
This study is copublished with a team led by Kathryn Wellen, PhD, of the University of Pennsylvania. Her lab showed that inhibiting the sugar scavenging pathway blocks tumor growth. Together, these studies demonstrate new opportunities through which to better understand the nuances of pancreatic cancer.
“People have been studying hyaluronic acid in pancreatic cancer for 20 years, and no one had ever thought to see if it could be a nutrient for cancer cells,” Dr. Lyssiotis said. “We’re going to dig deeper into this idea and see if it represents a therapeutic vulnerability that can be drugged.”
Disclosure: For full disclosures of the study authors, visit elifesciences.org.
