New Insights into How a Protein Facilitates Pancreatic Cancer’s Spread to Liver and Lungs

Researchers at the University of California, San Francisco have uncovered a key mechanism that explains how pancreatic cancer cells manage to colonize distant organs like the liver and lungs. These organs, which have vastly different environments—comparable to the ocean and desert ecosystems—pose unique challenges to cancer cells. Notably, metastasis to these organs is often the first sign of pancreatic cancer, but it typically indicates an advanced, uncontrollable stage.

This groundbreaking study, published in the journal Nature, opens new avenues for therapeutic development, especially given the notorious resistance of pancreatic cancer to existing treatments.

The research team analyzed data from the MetMap project at the Broad Institute, focusing on pancreatic cancer cell lines that tend to preferentially metastasize to either the liver or lungs. By examining genomic differences, they aimed to identify factors that drive organ-specific colonization.

A significant discovery was the role of the protein PCSK9, which regulates cholesterol uptake and production within cells. When PCSK9 levels are low, pancreatic cancer cells preferentially consume cholesterol from their environment—abundant in the liver—supporting their growth. Conversely, high PCSK9 levels lead the cells to produce their own cholesterol, facilitating survival in the lung environment. Additionally, cancer cells with elevated PCSK9 also produce molecules that shield them from oxygen-induced damage, an essential adaptation for surviving in lung tissue.

Experimental manipulation of PCSK9 confirmed its influence on metastatic behavior. When pancreatic cancer cells destined for the liver were made to overexpress PCSK9, they exhibited a tendency to metastasize to the lungs instead. According to lead researcher Rushika Perera, Ph.D., this indicates that cancer cells use PCSK9 to adapt to new environments during metastasis, offering a potential target for therapy that could disrupt this process by interfering with cholesterol acquisition.

This research not only enhances our understanding of pancreatic cancer metastasis but also suggests that targeting cholesterol metabolism pathways may be a promising strategy to combat metastatic disease. The findings highlight the complexity of cancer progression and the importance of cellular adaptation mechanisms in metastasis.

For more detailed information, the study can be accessed at https://www.nature.com/articles/s41586-025-09017-8.