New Findings Shed Light on Pancreatic Cancer Treatment Targets
Researchers have identified a protein that causes metastasis in pancreatic cancer—and a possible drug target to help treat the notoriously challenging disease
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 causes death, but little is known about the molecular mechanisms that drive metastasis.
In a new study published Dec. 18 in Advanced Science, researchers from the Department of Microbiology and Molecular Genetics showed that abnormal expression of the protein Engrailed-1 (EN1) 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, which suggests that EN1 might make a good potential target for pancreatic cancer therapies.
“We identified a novel epigenetic factor that can contribute to metastasis in pancreatic cancer, which is one of the most challenging cancers to treat,” says Chang-Il Hwang, an assistant professor in the Department of Microbiology and Molecular Genetics and a senior author on the paper. “A better understanding of these mechanisms would allow us to identify potential targets and improve patient survival.”
Uncovering a main actor in pancreatic metastasis
Metastasis is an important component of pancreatic cancer progression, but researchers have not been able to identify genetic mutations responsible for it. For this reason, Hwang thought that non-genetic factors, such as epigenetic changes or altered protein production, might be at play. His team previously identified several transcription factors—proteins that control the the production of other proteins— that are elevated in pancreatic cancers that have undergone metastasis 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 promote aggressive forms of breast cancer, and it is also associated with poor prognosis in other cancers, including glioblastoma and salivary gland adenoid cystic carcinoma, but its role in pancreatic cancer had not previously been delineated.
To determine EN1’s role in pancreatic cancer, the researchers tested whether inhibiting EN1 or ramping up its expression impacted the growth and survival of pancreatic cancer “organoids”—three-dimensional clumps of lab-grown tissue. They found that, without EN1, pancreatic cancer cells were less likely to survive and divide, but adding extra EN1 increased the tumors’ survival. Furthermore, when the researchers genetically modified mouse pancreatic cancer cell lines so that they produced more EN1 than usual, the cells showed increased rates of cell invasion and migration—key features of metastasis.
“It’s very clear that EN1 is a really important factor behind the aggressiveness of pancreatic cancer,” says first author Jihao (Reno) Xu, a Ph.D. candidate in the Biochemistry, Molecular, Cellular and Development Biology graduate group. “When we take the tumor cells and make them overexpress EN1, they become more metastatic and aggressive, and when we knock it down, they become less metastatic.”
By analyzing publicly available patient databases, the researchers also showed that EN1 is important for prognosis in human pancreatic cancer. They found that EN1 levels were elevated in a subset of patients with advanced pancreatic cancer, and that patients with elevated EN1 tended to have worse prognoses.
“Patients with high levels of EN1 have shorter survival times, which suggests that it is contributing to the aggressiveness of pancreatic cancer,” says Hwang.
Now, Hwang, Xu and their colleagues are working on ways to translate their findings into the clinic by testing different ways to target EN1 and the molecules that it interacts with. They also plan to continue investigating other non-genetic factors that might contribute to pancreatic cancer progression. “Ultimately, we want to identify new therapeutic strategies to tackle this disease,” says Xu.
Additional authors on the paper are: at UC Davis, EunJung Lee; Keely Y. Ji; Omar W. Younis; and Alexander D. Borowsky; Jae-Seok Roe, Yonsei University; Claudia Tonelli, Tim D.D. 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; and Jean L. Grem, Audrey J. Lazenby, James A. Grunkemeyer, Michael A. Hollingsworth, University of Nebraska Medical Center
The work was supported by the UC Davis Comprehensive Cancer Center Pilot Grant, the National Institutes of Health, the National Institute of Environmental Health Sciences, and the National Cancer Institute.