Scientists at Cold Spring Harbor Laboratory (CSHL) and the University of California, Davis have reached a breakthrough in pancreatic cancer research — eight years in the making. This can help reduce the deadly spread of the disease.

In 2017, as a postdoc in CSHL’s Tuveson lab, Chang-il Hwang and colleagues in the Vakoc lab uncovered a protein essential to jump-start metastasis in pancreatic ductal adenocarcinoma (PDAC). Now an assistant professor at UC Davis, Huang recently reunited with CSHL professors David Towson and Christopher Walkock. The trio once again set their sights on the PDAC. The disease is known for its aggressiveness. It often spreads to other organs like a wildfire, wreaking havoc in its path.

“Metastatic spread of pancreatic cancer is one of the causes of such a deadly disease. Our studies, led by Dr. Huang, have opened the door to new insights that we may one day use to combat aggressive PDAC.” can.”

The team found that late-stage PDAC hijacks a protein called Engrailed-1 (EN-1) to evade the body’s natural anti-cancer defenses. EN-1 is a type of protein called a transcription factor. These proteins control the timing and duration of gene expression. This specific transcription factor is required for the formation of large parts of the brain.

“EN-1 is known to play a role in neurodevelopment,” explains Huang. “In the pancreas, it’s not normally expressed. But in the later stages of pancreatic cancer, it becomes overexpressed and makes the cancer more metastatic.” This means a rapid, deadly spread. But what if EN-1 could be targeted in cancer? Huang, Tucson and Vakok tried to find out.

The team used organoids — miniature versions of tumors — to identify the role of overexpressed EN-1 in PDAC. They found that high levels of the abnormal protein inhibited genes associated with natural cell death. When the expression of EN-1 was reduced, the genes it targeted were able to do their job, promoting the survival of healthy cells.

“Without EN-1, cancer growth slows down,” Huang says. “Right now, targeting transcription factors with drugs is difficult. But in the future, it may be possible to disrupt the kind of interactions we see with mutated EN-1 in PDAC.”

Pancreatic cancer remains the third leading cause of cancer death in the U.S. Huang plans to continue collaborating with CSHL in hopes that his team’s work can lead to better treatments.

“We know that some types of PDAC are dependent on EN-1,” says Huang. “If we can develop a way to test for this, we can create more personalized treatments and treatment strategies for patients. We look forward to moving in that direction.”