Pancreatic cancer is one of the most lethal cancers, with only about 12% of patients surviving five years after diagnosis.
A key reason for its deadliness is the tumor’s tough environment: a thick layer of scar-like tissue, called fibrosis, surrounds the cancer, blocking treatments and shielding it from the immune system.
Now, scientists at the Salk Institute have found a way to weaken this protective barrier using a class of drugs known as HDAC inhibitors—offering hope for better treatment options.
The findings, published in Nature Communications, reveal that HDAC inhibitors don’t just slow the growth of cancer cells—they also target fibroblasts, the cells responsible for forming the dense scar tissue that wraps around pancreatic tumors.
Fibroblasts are normally helpful cells that support tissue structure and help heal injuries. But in the presence of a pancreatic tumor, they change their behavior.
They become overactive, creating thick fibrosis and sending signals that help the tumor grow. “Fibroblasts are double agents,” says Dr. Michael Downes, one of the study’s lead authors. “They try to contain the tumor but end up helping it thrive.”
To understand how to stop fibroblasts from fueling the tumor, the researchers tested HDAC inhibitors—experimental drugs that change how DNA is read inside cells.
HDACs (histone deacetylases) are enzymes that control access to specific genes by tightening or loosening DNA packaging. When HDACs are active, they allow fibroblasts to switch on genes that promote fibrosis and cancer support.
The team found that HDAC inhibitors do two important things:
- They stop fibroblasts from becoming overly active, reducing the buildup of scar tissue.
- They block the harmful signals that fibroblasts send to cancer cells, slowing down tumor growth.
In lab studies using isolated cells, and in live mice with pancreatic tumors, the HDAC inhibitor entinostat significantly lowered fibroblast activity and slowed tumor development. When they looked at data from human pancreatic cancer patients, they saw a clear pattern: patients with high levels of HDAC1 in their tumor’s fibrotic tissue had worse outcomes.
“This confirmed what we saw in the lab,” says Downes. “More HDAC activity means more aggressive disease. Blocking that activity helps.”
Rather than eliminating fibroblasts—which past studies found can make tumors more aggressive—the new approach focuses on calming them down.
“Fibroblasts themselves aren’t the enemy,” explains Dr. Annette Atkins, a co-author on the study. “But when they’re in overdrive, they do more harm than good. We found that just limiting their activation is enough to make a positive impact.”
The research also uncovered specific genes that HDAC inhibitors prevent from being activated in fibroblasts. These genes could be new targets for future therapies that fine-tune the fibroblast response without damaging healthy tissue.
While the results are promising, the researchers say there is still work to do. Pancreatic tumors are difficult to treat in part because their fibrotic walls are so dense that drugs struggle to reach them.
Scientists will now focus on finding better ways to deliver HDAC inhibitors directly to those areas—and explore how to combine them with other treatments like chemotherapy or immunotherapy for even greater effects.
“This dual-action approach—attacking both the tumor and its defenses—could be a game-changer for one of the hardest-to-treat cancers,” says senior author Dr. Ronald Evans. “It opens a new path forward in the fight against pancreatic cancer.”
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The research findings can be found in Nature Communications.
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