JACKSON — Scientists at the University of Mississippi Medical Center’s Cancer Center and Research Institute are working to understand how a protein present since the earliest stages of human development may help trigger one of the deadliest forms of pancreatic cancer.

Their study, now in the second year of a five-year, $1.8 million National Cancer Institute grant, focuses on pancreatic ductal adenocarcinoma, or PDAC. The cancer accounts for more than 90% of pancreatic cancer cases and is the third leading cause of cancer deaths in the United States. Because the disease is typically difficult to detect early and often resists treatment, PDAC survival rates remain low.

Dr. Keli Xu, associate professor of cell and molecular biology and a CCRI member, leads the research team. He said understanding how PDAC begins is key to developing better tools for diagnosis and treatment.

“Our goal is to identify the molecular mechanisms that drive PDAC from its earliest stages so we can intervene before the disease becomes aggressive and difficult to treat,” Xu said.

The team’s recent findings, published in Oncogene, suggest that pancreatic cells expressing a developmental protein called lunatic fringe, or Lfng, may act as a cell of origin for PDAC. Although Lfng plays a key role in shaping the embryo’s spine, ribs and skin layers, it continues to be expressed in parts of the adult body, including the pancreas.

Researchers found that high levels of Lfng are associated with poor survival in PDAC patients. In cancer development, Xu said, Lfng appears to work like a “turbocharger,” accelerating growth when paired with a signaling protein called Notch3. When combined with other genetic factors already known to promote cancer — such as an overactive Kras gene and a faulty tumor-suppressing p53 — the interaction can drive tumor formation.

UMMC scientists discovered that removing Lfng in pancreatic cells can slow or reduce tumor growth, and that blocking Notch3 signaling may help prevent the cancer from spreading. Those results point to potential new treatment approaches, including the use of gamma secretase inhibitors to turn off Notch3 signaling in aggressive or chemotherapy-resistant cases.

Traditional treatment options for PDAC — surgery, radiation and chemotherapy — have had limited success. Xu said targeted therapies developed from this research could eventually be used alongside existing approaches to improve outcomes and allow for earlier intervention.

“By understanding how PDAC starts at the cellular level, we can design therapies that stop it before it spreads,” Xu said. “This work could help us identify better biomarkers for early detection and develop drugs that specifically target the pathways driving tumor growth.”

Dr. Ajay Singh, professor of cell and molecular biology and CCRI associate director of basic and translational research, said the work could have lasting impact.

“His research is providing new insights into this lethal disease and has the potential to pave the way for targeted therapies and early detection strategies,” Singh said.

Xu, a UMMC cancer researcher and CCRI member for 14 years, holds a doctorate in biochemistry from Rutgers University and completed postdoctoral training in developmental and cancer biology at Toronto’s Hospital for Sick Children. His career has focused on how proteins crucial for embryonic development may later influence cancer development or suppression.

The NCI grant will allow Xu’s team to further investigate how Lfng, Notch3 and related signaling pathways contribute to PDAC. Ultimately, he said, the goal is to develop new diagnostic tools and therapies that improve survival for pancreatic cancer patients.

“Pancreatic cancer research has been challenging, but we’re at a turning point,” Xu said. “Research is bringing us closer to learning how this cancer starts and how we can stop it.”

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