Piercing the Shield: How HDAC Inhibitors Tackle Pancreatic Cancer’s Fibrotic Wall

Salk researchers discovered that an anti-cancer therapy can prevent the activation of fibroblasts, cells that typically form protective barriers around pancreatic tumors.

Pancreatic cancer is one of the deadliest cancers—only about one in eight patients survives five years after diagnosis. Those dismal statistics are in part due to the thick, nearly impenetrable wall of fibrosis, or scar tissue, that surrounds most pancreatic tumors and makes it hard for drugs to access and destroy the cancer cells.

Breakthrough in Pancreatic Cancer Treatment

Now, researchers at the Salk Institute have made a significant discovery. They found that HDAC inhibitors, a type of anti-cancer drug, can effectively treat pancreatic cancer by altering fibroblast activation. Fibroblasts create the scar tissue barrier around tumors.

The new research was published in Nature Communications<em>Nature Communications</em> is a peer-reviewed, open-access, multidisciplinary, scientific journal published by Nature Portfolio. It covers the natural sciences, including physics, biology, chemistry, medicine, and earth sciences. It began publishing in 2010 and has editorial offices in London, Berlin, New York City, and Shanghai. ” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>Nature Communications on December 6, 2023.

The abundance of cancer-associated fibroblasts (magenta) in the microenvironment with pancreatic cancer cells (green). Credit: Salk Institute

“These drugs turn out to be hitting both the tumor itself as well as the fibrotic tissue around it. This could be a very effective way to treat pancreatic cancers, which have typically been very difficult to reach,” says senior author Professor Ronald Evans, director of Salk’s Gene Expression Laboratory and March of Dimes Chair in Molecular and Developmental Biology.

Role of Fibroblasts in Pancreatic Cancer

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. 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.

“In the context of most pancreatic cancers, fibroblasts are acting as both good players and bad players,” says Michael Downes, senior staff scientist and co-corresponding author on the paper. “It’s a double-edged sword.”

HDAC Inhibitors’ Impact on Fibroblasts

In the new research, the team probed the effect on fibroblasts of an experimental class of cancer drugs known as histone deacetylase (HDAC) inhibitors. HDACs alter the three-dimensional structure of DNADNA, or deoxyribonucleic acid, is a molecule composed of two long strands of nucleotides that coil around each other to form a double helix. It is the hereditary material in humans and almost all other organisms that carries genetic instructions for development, functioning, growth, and reproduction. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>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.

In experiments on isolated cells, the researchers discovered that HDAC inhibitors prevented fibroblasts from becoming activated and tumor supportive.

From left: Yang Dai, Gabriela Estepa, Ruth Yu, Tony Hunter, Michael Downes, Annette Atkins, Yuwenbin Li, Gaoyang Liang, Dylan Nelson, and Ronald Evans. Credit: Salk Institute

Promising Results From HDAC Inhibitor Research

“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,” says Gaoyang Liang, first author and research associate in Evans’ lab.

In mice, the researchers found that one experimental HDAC inhibitor, entinostat, both reduced the activation of fibroblasts around pancreatic tumors and slowed tumor growth. When the researchers analyzed data from humans with pancreatic cancer, they discovered something similar: the higher the levels of HDAC1 in the fibrotic tissue around a patient’s tumor, the worse their outcome.

“This is in agreement with what we saw in cells and in mice,” says Downes. “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.”

Future Directions in Cancer Treatment

Since HDAC inhibitors work by preventing cells from activating certain genetic programs, 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.

“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,” says Annette Atkins, co-author of the study and senior research scientist in Evans’ lab. “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.

Reference: “Inhibiting stromal class I HDACs curbs pancreatic cancer progression” 6 December 2023, Nature Communications.
DOI: 10.1038/s41467-023-42178-6

Other authors of the paper are Tae Gyu Oh, Nasun Hah, Yu Shi, Morgan L. Truitt, Corina E. Antal, Annette R. Atkins, Yuwenbin Li, Antonio F. M. Pinto, Dylan C. Nelson, Gabriela Estepa, Senada Bashi, Ester Banayo, Yang Dai, Ruth T. Yu, Tony Hunter, and Dannielle D. Engle of Salk; Hervé Tiriac of UC San Diego; Cory Fraser of HonorHealth Scottsdale; Serina Ng, Haiyong Han, and Daniel D. Von Hoff of The Translational Genomic Research Institute; and Christopher Liddle of the University of SydneyThe University of Sydney is a public research university located in Sydney, New South Wales, Australia. Founded in 1850, it is the oldest university in Australia and is consistently ranked among the top universities in the world. The University of Sydney has a strong focus on research and offers a wide range of undergraduate and postgraduate programs across a variety of disciplines, including arts, business, engineering, law, medicine, and science.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>University of Sydney.

The work was supported by grants from the Lustgarten Foundation (including award 552873), Don and Lorraine Freeberg Foundation, Ipsen Bioscience, a Stand Up To Cancer-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (SU2C-AACR-DT-20-16), a Ruth L. Kirschstein National Research Service Award (F32CA217033), a Life Sciences Research Foundation Fellowship, the Damon Runyon Cancer Research Foundation (DRG-2244-16), the National Institutes of HealthThe National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. Founded in 1887, it is a part of the U.S. Department of Health and Human Services. The NIH conducts its own scientific research through its Intramural Research Program (IRP) and provides major biomedical research funding to non-NIH research facilities through its Extramural Research Program. With 27 different institutes and centers under its umbrella, the NIH covers a broad spectrum of health-related research, including specific diseases, population health, clinical research, and fundamental biological processes. Its mission is to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.” data-gt-translate-attributes=”[{“attribute”:”data-cmtooltip”, “format”:”html”}]” tabindex=”0″ role=”link”>National Institutes of Health (CA082683, 5T32CA009370), and the William Isacoff Research Foundation.