Key Factor in Pancreatic Cancer Cell Survival in Distinct Environments

Researchers at the University of California, San Francisco, have identified how pancreatic cancer cells adapt to grow in the lungs or liver, two organs with very different environments. The spread of pancreatic cancer to these organs often marks the first noticeable symptoms of the disease. By that stage, however, the cancer is typically already advanced.

The findings, published in Nature on May 21, 2025, may help inform new treatment strategies for pancreatic cancer, which is difficult to treat with current therapies. The study was partially funded by the National Institutes of Health (NIH), the National Science Foundation (NSF), and the American Association for Cancer Research.

The researchers aimed to understand why certain cancer cells survive better in specific organs. To investigate this, they used data from MetMap, a project based at the Broad Institute, to identify pancreatic cancer cell lines that tend to colonize either the lungs or the liver. They then looked for genomic differences that might explain this organ preference.

Their analysis identified a protein called PCSK9, which affects how cells absorb cholesterol. When PCSK9 levels are low, pancreatic cancer cells rely on the liver’s high cholesterol supply. When PCSK9 levels are high, cells produce their own cholesterol and generate molecules that help protect them from oxygen-related damage—an adaptation better suited for the lung environment.

When the researchers caused liver-targeting pancreatic cancer cells to produce PCSK9, the cells shifted their growth toward the lungs instead.

Cancers persist by adapting to live in new tissues and organs, and we found that pancreatic tumors use PCSK9 to adapt as they spread. It opens the door to fighting metastatic cancer growth by manipulating how cells acquire their cholesterol.”

Rushika Perera, Ph.D., Study Senior Author and Deborah Cowan Endowed Associate Professor of Anatomy, University of California, San Francisco