Severe pancreatic cancer is associated with metastasis, which is the spread of secondary tumors that usually cause death. Little is known about the molecular mechanisms that drive metastasis.
Now, UC Davis researchers have found that abnormal expression of the protein Engrailed-1 (EN1) promotes pancreatic cancer progression and metastasis in artificial samples and in mice. The team also found that elevated EN1 was associated with severe, metastatic pancreatic cancer in human patients. This suggests that EN1 might make a good target for pancreatic cancer therapies. The work was supported by a UC Davis Comprehensive Cancer Center pilot grant and the National Institutes of Health.
“We identified a novel epigenetic factor that can contribute to metastasis in pancreatic cancer, which is one of the most challenging cancers to treat,” said Chang-il Hwang, an assistant professor in the UC Davis 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.”
Epigenetic changes are modifications in gene activity without changes in DNA sequencing.
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 nongenetic factors, such as epigenetic changes or altered protein production, might be at play. His team previously identified several transcription factors — proteins that control 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. It is also associated with poor prognosis in other cancers, including glioblastoma and salivary gland adenoid cystic carcinoma. However, its role in pancreatic cancer had not yet been described.
with experimentally depleted levels of EN1,
which reduces metastatic activity (Jihao Xu).
The researchers tested whether inhibiting EN1 or ramping up its expression impacted the growth and survival of pancreatic cancer “organoids” — three-dimensional clumps of labgrown tissue. They found that, without EN1, pancreatic cancer cells were less likely to survive and divide, but adding extra EN1 increased the tumors’ survival. Next, the researchers genetically modified mouse pancreatic cancer cell lines so that they produced more EN1 than usual. They found that 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,” said first author Jihao (Reno) Xu, a doctoral candidate in the Biochemistry, Molecular, Cellular and Developmental 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.”
Additional scientists involved in the research included: EunJung Lee, Keely Y. Ji, Omar W. Younis and Alexander D. Borowsky, UC Davis; Jae-Seok Roe, Yonsei University; Claudia Tonelli, Tim D.D. Somervile, 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.
Teaming up to take on pancreatic cancer
The UC Davis Comprehensive Cancer Center is hoping to dramatically change outcomes for pancreatic cancer patients. The cancer center has joined the UC Pancreatic Cancer Center, which brings together all of the five University of California comprehensive cancer centers to fight pancreatic cancer. This includes sharing research, coordinating trials, developing therapies and treating and educating patients about this often-fatal cancer.
