Researchers identify protein linked to metastasis in pancreatic cancer

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States, and only 12% of patients survive five years after being diagnosed. Severe pancreatic cancer is associated with metastasis, and it is this spread of secondary tumors that usually results in death, but little is known about the molecular mechanisms causing metastasis.

In a study published on December 18 in Advanced scienceresearchers at the University of California, Davis, showed that abnormal expression of the protein Engraved-1 (FR1) promotes pancreatic cancer progression and metastasis in vitro and in mouse models. The team also found that an increase FR1 has been associated with severe metastatic pancreatic cancer in human patients, suggesting that FR1 could be a good target for therapies against pancreatic cancer.

“We identified a new epigenetic factor that may contribute to metastasis of pancreatic cancer, which is one of the most difficult cancers to treat,” said Chang-Il Hwang, assistant professor in the Department of Microbiology and Molecular Genetics at UC Davis and principal investigator. author on paper. “A better understanding of these mechanisms would allow us to identify potential targets and improve patient survival.”

Discovering a main player in pancreatic metastases

Metastasis is an important part of pancreatic cancer progression, but researchers have not been able to identify the genetic mutations that cause it. For this reason, Hwang believed that non-genetic factors, such as epigenetic changes or altered protein production, might be at play. His team had previously identified several transcription factors – proteins that control the production of other proteins – which are elevated in pancreatic cancers that have metastasized compared to primary tumors.

One of these proteins, FR1is essential for neuronal survival during development and is generally not produced in adult pancreatic cells. FR1 It has been shown to promote aggressive forms of breast cancer and is also associated with poor prognosis in other cancers, including glioblastoma and adenoid cystic carcinoma of the salivary glands, but its role in cancer of the pancreas had not been previously described.

The researchers tested whether inhibition FR1 or increased expression impacted the growth and survival of pancreatic cancer “organoids” – three-dimensional clumps of tissue grown in the laboratory. They found that, without FR1pancreatic cancer cells were less likely to survive and divide, but by adding FR1 increased tumor survival. Additionally, when researchers genetically engineered mouse pancreatic cancer cell lines so that they produced more FR1 than usual, cells exhibited increased rates of cell invasion and migration, key features of metastasis.

“It is very clear that FR1 is a very important factor behind the aggressiveness of pancreatic cancer,” said first author Jihao (Reno) Xu, a doctoral student in the biochemistry, molecular, cellular and developmental biology graduate group. FR1they become more metastatic and aggressive, and when we knock them down, they become less metastatic. »

By analyzing publicly available patient databases, the researchers also showed that FR1 is important for the prognosis of human pancreatic cancer. They found that FR1 rates were elevated in a subgroup of patients with advanced pancreatic cancer, and that patients with elevated pancreatic cancer FR1 tended to have poorer prognoses.

“Patients with high levels of FR1 have shorter survival times, suggesting that it contributes to the aggressiveness of pancreatic cancer,” Hwang said.

Today, Hwang, Xu and their colleagues are working on ways to translate their findings to the clinic by testing different ways to target FR1. They also plan to continue studying other non-genetic factors that may contribute to the progression of pancreatic cancer.

“Ultimately, we want to identify new therapeutic strategies to combat this disease,” Xu said.