Scientists at the University of California, San Francisco (UCSF) have uncovered a fundamental biological mechanism that explains how pancreatic cancer cells successfully colonize different organs during metastasis. The study, which identifies a protein known as PCSK9 as a master regulator of this process, offers a new perspective on how one of the world’s most lethal cancers adapts to vastly different physiological environments. By understanding how these cells transition between the nutrient-rich environment of the liver and the oxygen-heavy atmosphere of the lungs, researchers believe they have found a potential vulnerability in a disease that has long been considered notoriously resistant to conventional therapies.
The findings, published on May 21 in the prestigious journal Nature, address one of the most challenging aspects of oncology: the ability of cancer cells to thrive in environments that are as distinct to a cell as the ocean and the desert are to terrestrial animals. In the case of pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, this adaptability is particularly deadly. Often, the spread of cancer cells to distant organs like the lungs or the liver produces the very first symptoms a patient might notice. Unfortunately, by the time these symptoms manifest, the cancer has typically spread out of control, making surgical intervention difficult and significantly reducing the efficacy of existing treatments.
The research team, led by senior author Rushika Perera, PhD, who serves as the Deborah Cowan Endowed Associate Professor of Anatomy at UCSF, sought to understand the metabolic "logic" behind this organ-specific colonization. To do so, they turned to a wealth of existing data from MetMap, a comprehensive project hosted by the Broad Institute, an independent research organization. MetMap serves as a repository of information regarding the metastatic potential of various cancer cell lines, allowing scientists to track where specific cells are likely to travel and survive within the body. By analyzing this data, the UCSF team identified specific pancreatic cancer cell lines that demonstrated a clear preference for either the lung or the liver.
Once these cell lines were categorized by their destination preference, the researchers performed a deep genomic analysis to uncover the differences that allowed these cells to choose—and survive in—one organ over the other. Their investigation led them to a protein called PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9). While PCSK9 is well-known in the medical community for its role in regulating cholesterol levels in the blood, its role as a switch for cancer metastasis represents a significant shift in how scientists view the protein’s function.
The study revealed that PCSK9 acts as a metabolic thermostat, controlling how pancreatic cancer cells obtain the cholesterol they need to build their outer membranes and fuel their growth. The availability of cholesterol varies wildly depending on the organ. The liver, for example, is the body’s primary factory for cholesterol, making it a target-rich environment for cancer cells. The lungs, conversely, are cholesterol-poor but high in oxygen, presenting a different set of survival challenges.
