Team discovers key player in the spread of pancreatic cancer

Researchers have identified a protein linked to pancreatic cancer metastasis.

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 new study in Advanced scienceResearchers from the University of California, Davis, show that abnormal expression of the Engrailed-1 (EN1) protein promotes pancreatic cancer progression and metastasis in vitro and in mouse models.

The team also found that elevated EN1 was associated with severe metastatic pancreatic cancer in human patients, suggesting that EN1 could be a good target for pancreatic cancer therapies.

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

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 previously identified several protein transcription factors that control the production of other proteins that are elevated in pancreatic cancers that have metastasized compared to primary tumors.

One of these proteins, EN1, is essential for neuronal survival during development and is generally not produced in adult pancreatic cells. EN1 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 Pancreatic cancer had not been previously described.

The researchers tested whether inhibiting EN1 or increasing its expression impacted the growth and survival of pancreatic cancer “organoids,” three-dimensional clumps of tissue grown in the lab. They found that without EN1, pancreatic cancer cells were less likely to survive and divide, but adding extra EN1 increased tumor survival. Additionally, when researchers genetically engineered mouse pancreatic cancer cell lines so that they produced more EN1 than usual, the cells exhibited increased rates of invasion and cell migration, key features of metastases.

“It is very clear that EN1 is a very important factor behind the aggressiveness of pancreatic cancer,” says first author Jihao (Reno) Xu, a doctoral student in the Biochemistry, Molecular, Cellular and Developmental Biology graduate group. . “When we take tumor cells and make them overexpress EN1, they become more metastatic and aggressive, and when we kill them, they become less metastatic.”

By analyzing publicly available patient databases, the researchers also showed that EN1 is important for the prognosis of human pancreatic cancer. They found that EN1 levels were elevated in a subgroup of patients with advanced pancreatic cancer and that patients with elevated EN1 tended to have a poorer prognosis.

“Patients with high levels of EN1 have a shorter survival time, suggesting that this contributes to the aggressiveness of pancreatic cancer,” says Hwang.

Now, Hwang, Xu and their colleagues are working on ways to translate their findings to the clinic by testing different ways to target EN1. 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,” says Xu.

Other authors on the paper are from UC Davis, Yonsei University, Cold Spring Harbor Laboratory, Cornell University and the University of Nebraska Medical Center.

Support for the work came from the pilot grant from the UC Davis Comprehensive Cancer Center and the National Institutes of Health.

Source: University of California, Davis