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Under the Microscope: Intercepting secret messages to fight pancreatic cancer

Researchers have worked tirelessly for decades to find new therapies for pancreatic cancer, yet it remains a difficult disease to treat. In fact, in 2016, pancreatic replaced breast cancer as the third leading cause of cancer-related deaths in the U.S.

“There have been significant strides in understanding the genetics of pancreatic cancer,” said Mara Sherman, Ph.D., from the Oregon Health & Science University Knight Cancer Institute. “However, it is becoming clear that we need to know more about the biology of this cancer to develop more effective treatments.”

With V Foundation funding, Sherman is moving science closer to understanding the biological pathways that make pancreatic tumors tick. Among cancers, one thing that sets pancreatic tumors apart is their unusual microenvironment. Only a small portion of the tumor consists of cancer cells—malignant cells with mutated DNA. Most of the tumor is made of scar-like tissue that nurtures the cancer cells while shielding them from anti-cancer drugs. Sherman said she believes understanding the inner workings of this protective tissue could be key to developing new therapies for pancreatic cancer.

Looking to the stars

Sherman’s research focuses on stellate cells, which are shaped like tiny stars. In healthy tissue, these cells help to heal damage in the pancreas, liver and other organs by transforming themselves into scar-forming cells called myofibroblasts. They also are the body’s storage lockers for vitamin A, which they carry inside small droplets of fat, or lipid.

Stellate cells respond to a tumor the same way they respond to tissue damage, by creating scar tissue. Unfortunately, in the case of pancreatic cancer, it seems this process may only make the situation worse.

My previous work showed that lipid storage and metabolism change profoundly in stellate cells during pancreatic tumor progression. In this new work, we wanted to understand the potential significance of this and whether this switch may somehow help pancreatic cells survive.

Mara Sherman, Ph.D.

Working with Jurre Kamphorst from the Beatson Institute in the U.K., Sherman and her team found fibroblasts from human pancreatic tumors secrete high levels of lipids. Using mouse models, they also observed pancreatic cancer cells take up these lipids. These findings suggest stellate cells are essentially feeding the cancer by spitting out fat droplets.

Following the trail further, the researchers discovered the lipids are also metabolized, or digested, by autotaxin, an enzyme secreted from pancreatic cancer cells. This process creates a molecular signal that urges the cancer cells to keep growing.

While it would likely be hard to stop stellate cells from feeding their lipids to cancer cells, stopping autotaxin is much more feasible. In fact, there are already drugs on the market that inhibit autotaxin. To find out how inhibiting autotaxin would affect the cancer, the researchers blocked the enzyme using two different methods: drugs and genetic manipulation. Although both approaches slowed pancreatic tumor progression in mice, the genetic inhibition was much more potent. This could mean the drug wasn’t getting delivered efficiently, or that a better drug is needed.

Targeting the ‘puppet master’

The researchers are continuing to study how inhibiting autotaxin affects pancreatic cancer cells and the tumor microenvironment. “If we better understand the consequences of autotaxin inhibition, perhaps we can come up with a combination of therapeutic strategies that will be more efficient than targeting autotaxin alone,” said Sherman. “Understanding the cell type that’s the puppet master of this reaction may help us figure out which pathways or molecules to target therapeutically.”

To do this, the researchers are developing new mouse models that will allow them to turn off specific cell types, enabling them to see what happens to other cells within the tumor microenvironment when certain cells are inactivated.

“When we applied for the V Foundation funding, we didn’t know if the process we were studying would actually impact tumor progression,” said Sherman. “The support allowed us to get preliminary data, which led to an NIH grant that is allowing us to continue this line of study.”

Sherman said she hopes that within the next five to 10 years their research will reveal a combination of drugs that is promising enough to move into clinical testing.