Pancreatic cancer is the third leading cause of cancer-related death in the United States, with only 12% of patients surviving five years after diagnosis. Advanced pancreatic cancer is associated with metastasis, which typically leads to death. However, little is known about the molecular mechanisms driving metastasis.
In a study published on December 18th in Advanced Science, researchers at the University of California, Davis demonstrated abnormal expression of the protein Engrailed-1 (EN1) promotes the progression and metastasis of pancreatic cancer in vitro and in mouse models. The team also found that increased EN1 was associated with human patients with advanced, metastatic pancreatic cancer, suggesting that EN1 could be a good target for pancreatic cancer therapy.
„We have identified a novel epigenetic factor that may contribute to metastasis in pancreatic cancer, one of the most difficult-to-treat types of cancer. A better understanding of these mechanisms would allow us to identify potential points of attack and improve patient survival.“
Chang-Il Hwang, Assistant Professor at the Department of Microbiology and Molecular Genetics, UC Davis and lead author of the article
Identification of a Key Player in Pancreatic Metastasis
Metastasis is a critical component of pancreatic cancer progression. However, researchers have been unable to identify genetic mutations responsible for it. Therefore, Hwang suspected that non-genetic factors such as epigenetic changes or altered protein production might play a role. His team previously identified several transcription factors—proteins that control the production of other proteins—that were increased in pancreatic cancers that had metastasized compared to primary tumors.
One of these proteins, EN1, is essential for the survival of neurons during development and is not usually produced in adult pancreatic cells. EN1 has been shown to favor aggressive forms of breast cancer and is also associated with poor prognosis in other types of cancer. While its role in pancreatic cancer had not been described previously, the researchers tested whether inhibiting EN1 or increasing its expression affected the growth and survival of pancreatic cancer „organoids“—three-dimensional clumps of tissue grown in the laboratory. They found that without EN1, the likelihood of survival and division of pancreatic cancer cells was lower, whereas increased EN1 improved tumor survival. Moreover, the researchers genetically manipulated mouse pancreatic cancer cell lines to produce more EN1 than usual, and found that the cells showed an increased rate of invasion and migration, key features of metastasis.
„It’s quite clear that EN1 is a very important factor for the aggressiveness of pancreatic cancer,“ said lead author Jihao (Reno) Xu, a graduate student in Biochemistry, Molecular, Cellular, and Developmental Biology. „When we take tumor cells and overexpress EN1, they become more metastatic and aggressive, and if we knock it down, they become less metastatic.“
The researchers also analyzed publicly available patient databases and found that EN1 is important for human pancreatic cancer prognosis. Higher EN1 levels were associated with a worse prognosis in patients with advanced pancreatic cancer, indicating that high EN1 levels contribute to the aggressiveness of pancreatic cancer.
Now, Hwang, Xu, and their colleagues are working to translate their findings into the clinic by testing various targeting methods for EN1. They also plan to further investigate other non-genetic factors that may contribute to pancreatic cancer progression.
„Ultimately, we want to identify new therapeutic strategies to combat this disease,“ said Xu.
Other authors of the article are: EunJung Lee, Keely Y. Ji, Omar W. Younis, and Alexander D. Borowsky at UC Davis; Jae-Seok Roe, Yonsei University; Claudia Tonelli, Tim DD Somerville, Melissa Yao, Joseph P. Milazzo, Herve Tiriac, Youngkyu Park, Christopher R. Vakoc, and David A. Tuveson, Cold Spring Harbor Laboratory; Ania M. Kolarzyk and Esak Lee, Cornell University; Jean L. Grem, Audrey J. Lazenby, James A. Grunkemeyer, and Michael A. Hollingsworth, University of Nebraska Medical Center.
The work was supported by the UC Davis Comprehensive Cancer Center Pilot Grant and the National Institutes of Health.
Source: University of California – Davis
Journal Reference: Xu, J., et al. (2023). Engrailed-1 promotes the metastasis of pancreatic cancer. Advanced Science. doi.org/10.1002/advs.202308537.