In a groundbreaking study published May 21 in Nature, scientists at UC San Francisco have identified a protein that plays a crucial role in how pancreatic cancer cells spread to other organs—one of the deadliest and most elusive aspects of this disease.
The protein, called PCSK9, appears to act like a navigation system for metastatic cancer cells, determining whether they thrive in the lungs or liver—two vastly different environments within the body.
This discovery not only provides a deeper understanding of how pancreatic cancer spreads but also introduces a promising new strategy for treatment by targeting how cancer cells manage cholesterol.
Pancreatic cancer is often not discovered until it has already metastasized, meaning it has spread to other organs. At this point, treatment becomes extremely difficult, and patient survival rates drop sharply. Understanding what allows these cancer cells to survive and grow in distant organs is critical to finding more effective therapies.
To unravel this mystery, the UCSF team used data from MetMap, a research project at the Broad Institute that tracks how different cancer cell lines spread to various organs. The researchers focused on pancreatic cancer cell lines that preferred to colonize either the liver or the lungs.
They then searched for genetic clues that might explain why these cells settled in one organ and not the other.
What they found was striking: PCSK9 influenced how the cancer cells acquired cholesterol, a substance critical for cell survival and growth. Cholesterol is especially plentiful in the liver, and when PCSK9 levels are low, pancreatic cancer cells absorb this cholesterol directly from their surroundings.
In contrast, when PCSK9 levels are high, the cells produce their own cholesterol and also create protective molecules that help them survive the oxygen-rich environment of the lungs.
Even more compelling, when scientists genetically modified liver-targeted cancer cells to increase PCSK9, the cells changed course and began spreading to the lungs instead. This suggests that PCSK9 is not just a marker of where cancer cells might go—it actually controls their behavior and adaptability in different organ environments.
“Cancers persist by adapting to live in new tissues and organs,” said Dr. Rushika Perera, senior author of the study and a leading researcher in cancer cell biology at UCSF. “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.”
The implications of this discovery are far-reaching. By understanding how PCSK9 helps cancer cells adapt and survive in new environments, researchers may be able to block or redirect this process, potentially stopping metastasis in its tracks.
Targeting PCSK9 could become a way to interfere with the cancer’s ability to spread, a critical step toward improving survival rates for pancreatic cancer, which remains one of the most lethal forms of cancer.
The study was supported by funding from the National Institutes of Health (NIH), the National Science Foundation (NSF), and the American Association for Cancer Research, highlighting the growing urgency to find innovative solutions for this devastating disease.
While more research is needed to test how manipulating PCSK9 might work in patients, this discovery represents a significant advance in the fight against metastatic pancreatic cancer. It also underscores the importance of understanding how tumors interact with their environment—and how a single protein can change the course of a deadly disease.
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The research findings can be found in Nature.
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