Most pancreatic tumors are surrounded by a thick, nearly impenetrable wall of fibrosis— scar tissue—that makes it hard for drugs to access and destroy the cancer cells. Researchers at the Salk Institute have now discovered how a class of anticancer drugs called histone deacetylase (HDAC) inhibitors (HDACi) can help treat pancreatic cancer by modulating the activation of fibroblasts, which are the cells that make up that wall of scar tissue. Tests in mouse cancer models showed that treatment with an HDACi reduced disease severity.

“These drugs turn out to be hitting both the tumor itself as well as the fibrotic tissue around it,” said professor Ronald Evans, PhD, director of Salk’s Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology. “This could be a very effective way to treat pancreatic cancers, which have typically been very difficult to reach.” Evans is senior author of the team’s published paper in Nature Communications, titled “Inhibiting stromal Class I HDACs curbs pancreatic cancer progression.”

Pancreatic ductal adenocarcinoma (PDAC) cancer has a “dismal” survival rate, the authors noted, and is predicted to become the second most lethal cancer by 2030. In response to a new pancreatic tumor, the pancreas typically activates fibroblasts—the connective cells that support the structure of most organs. When flipped from a resting state to an active state, fibroblasts build a thick layer of scar tissue around the cancer.

From left: Yang Dai, Gabriela Estepa, Ruth Yu, Tony Hunter, Michael Downes, Annette Atkins, Yuwenbin Li, Gaoyang Liang, Dylan Nelson, and Ronald Evans. [Salk Institute]
From left: Yang Dai, Gabriela Estepa, Ruth Yu, Tony Hunter, Michael Downes, Annette Atkins, Yuwenbin Li, Gaoyang Liang, Dylan Nelson, and Ronald Evans. [Salk Institute]
While this normal protective mechanism can help wall off a cancer and prevent its spread, fibroblasts also produce signaling molecules that the tumor itself takes advantage of to grow. Michael Downes, PhD, senior staff scientist and co-corresponding author on the paper, added, “In the context of most pancreatic cancers, fibroblasts are acting as both good players and bad players. It’s a double-edged sword.”

So with respect to PDAC, the authors explained further, “The poor prognosis and therapeutic resistance have been in part attributed to the prominent activated stroma resulting from a desmoplastic response induced by the transformed pancreatic epithelium. The desmoplastic response is largely due to the activation of fibroblast-like cells, including pancreatic stellate cells (PSCs), the major resident fibroblasts in pancreatic stroma … Approaches designed to reduce pro-desmoplastic and pro-tumorigenic features in stromal fibroblasts without ablating the tumor-stroma architecture could provide a potentially safe and effective strategy to improve therapeutic outcome.”

In the new research, the team probed the effect on fibroblasts of an experimental class of cancer drugs known as HDAC inhibitors. HDACs alter the three-dimensional structure of DNA inside cells, making some stretches of DNA easier or harder for other molecules to access and read. Targeting HDACs can therefore prevent cells from making large changes to their behavior, such as the out-of-control growth of cancer cells. But how the drugs work on all cell types is not well understood. “While HDACs in pancreatic tumor cells have been associated with PDAC development, the role of HDACs in stromal fibroblasts is poorly understood and the therapeutic potential of HDACi, in particular, the stromal modulating potential remains to be fully explored,” the investigators stated.

Through experiments on isolated cells, the researchers discovered that HDAC inhibitors prevented fibroblasts from becoming activated and tumor supportive. “Using HDAC inhibitors actually did two things—it both turned down the growth signals from the fibroblasts to the cancer cells and it reduced the actual activation and accumulation of the fibroblasts,” said Gaoyang Liang, PhD, first author and research associate in Evans’ lab.

The abundance of cancer-associated fibroblasts (magenta) in the microenvironment with pancreatic cancer cells (green).
The abundance of cancer-associated fibroblasts (magenta) in the microenvironment with pancreatic cancer cells (green). [Salk Institute]
Through studies in mice, the researchers also found that one experimental HDAC inhibitor, entinostat, both reduced the activation of fibroblasts around pancreatic tumors and slowed tumor growth. And when the researchers analyzed data from humans with pancreatic cancer, they discovered that the higher the levels of HDAC1 in the fibrotic tissue around a patient’s tumor, the worse the patient’s outcome. Downes commented, “This is in agreement with what we saw in cells and in mice. If you have more HDAC activities in the fibroblasts, you have a worse outcome. On the other hand, if you inhibit the HDACs, you have a better outcome.” The authors also stated in their paper, “The fact that stromal HDAC expression predicts poor prognosis in PDAC patients further supports the essential roles of stromal HDACs in contributing to PDAC progression.”

HDAC inhibitors work by preventing cells from activating certain genetic programs, and the researchers wanted to know which stretches of DNA impacted by the drugs were most relevant for fibroblast activation. They identified several genes that HDAC inhibitors prevent from being expressed—suggesting that new drugs could target those genes to keep fibroblasts from becoming activated and promoting cancer growth and fibrosis. In conclusion, the team noted, “our study uncovers important roles of HDACs in regulating the transcriptional programs driving stromal activation and pro-tumorigenicity and provides the scientific foundation for using HDACi as a potent stromal targeting strategy.”

Co-author Annette Atkins, PhD, who is a senior research scientist in Evans’ lab, pointed out, “There have been some questions in the past about whether targeting fibroblasts is a good thing or a bad thing in pancreatic cancers, because people have shown that if you get rid of fibroblasts altogether it actually makes the cancers more aggressive. “But what our results suggest is that we don’t have to get rid of them; just limiting their activation is beneficial.”

More work is needed to pinpoint how to best deliver HDAC inhibitors to the dense fibrotic tissue around pancreatic tumors, as well as how they might be most effectively combined with other cancer treatments. As the authors suggested, “Along with recent findings that HDAC inhibitors sensitize tumors to immune checkpoint blockades and other epigenetic agents, our data highlight the potential of this class of epigenetic modulators in PDAC therapeutics. Strategies to boost the efficacy of HDACi should be developed in a quest for successful clinical translation.”

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