Scientists have discovered a key protein that acts like a GPS for pancreatic cancer cells, guiding them to the liver or lungs and opening up new possibilities to halt the disease’s deadly spread.
Key Points at a Glance
- PCSK9 protein controls how pancreatic cancer cells adapt to either liver or lung environments
- Low PCSK9 levels help cancer cells thrive in the liver by consuming local cholesterol
- High PCSK9 levels allow cells to produce cholesterol and survive oxidative stress in the lungs
- Manipulating PCSK9 expression may provide a way to prevent or redirect metastasis
- Findings offer a promising new strategy for tackling the deadliest phase of pancreatic cancer
For most people, pancreatic cancer shows no symptoms until it’s too late. What finally alerts doctors to the disease is often its silent spread to other organs. But why do some tumors set up shop in the liver while others migrate to the lungs? A new study from UC San Francisco reveals that a single protein, PCSK9, may be the mastermind behind these deadly decisions.
In groundbreaking research published in Nature, UCSF scientists uncovered how PCSK9 acts as a metabolic switch, helping pancreatic cancer cells adapt to vastly different environments — much like animals evolving for life in either desert or ocean. The liver and lungs, while both common sites of metastasis, pose entirely different challenges to migrating cancer cells. Understanding how those cells survive and thrive in such divergent habitats has long puzzled researchers.
The UCSF team turned to the MetMap database at the Broad Institute to analyze pancreatic cancer cell lines and their preferred metastatic destinations. By comparing the genetic makeup of these cells, they discovered that PCSK9 was consistently linked to organ-specific behavior. When PCSK9 levels were low, cancer cells gravitated toward the liver, feasting on its cholesterol-rich environment. Conversely, cells with high PCSK9 levels avoided the liver and instead took up residence in the lungs, where they produced their own cholesterol and developed defenses against the oxidative stress in the air-filled tissue.
“Cancers persist by adapting to live in new tissues and organs,” said Dr. Rushika Perera, senior author of the study. “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.”
To test this, the team genetically altered liver-destined pancreatic cancer cells to express high levels of PCSK9. Remarkably, this forced the cells to change course — they ended up in the lungs instead. In animal models, color-coded cancer cells revealed striking organ preferences depending on their PCSK9 expression. “KP4” cells with low PCSK9 colonized the liver, while “HPAC” cells with high PCSK9 settled in the lungs.
These findings don’t just deepen our understanding of cancer biology — they offer hope. Pancreatic cancer is notoriously resistant to most therapies, and once it spreads, survival rates plummet. But now, with PCSK9 in the spotlight, scientists can begin to explore new strategies that manipulate its activity. It might be possible to steer cancer cells away from vital organs or even make them more vulnerable to existing treatments by disrupting their cholesterol pathways.
The implications reach far beyond pancreatic cancer. PCSK9 is already well-known in cardiology circles as a target for cholesterol-lowering drugs. This overlap could accelerate the development of anti-metastatic therapies by repurposing or adapting medications already on the market.
As science continues to unravel the complex decision-making processes of cancer cells, studies like this shine a light on molecular levers we can potentially pull to control the disease. It’s a rare glimpse into the inner logic of metastasis — and a promising step toward outsmarting one of the deadliest cancers known to medicine.
