Longevity & AgingPCSK9 Controls Where Pancreatic Cancer Spreads by Regulating Cholesterol
Researchers discovered that PCSK9, a protein best known for regulating cholesterol, acts as a master switch determining whether pancreatic ductal adenocarcinoma (PDAC) cells preferentially colonize the liver or lungs. Low-PCSK9 tumor cells maintain high LDL receptors, avidly absorb cholesterol-rich LDL from liver tissue to fuel mTORC1-driven growth, and remodel the hepatic microenvironment. High-PCSK9 lung-avid cells instead synthesize their own cholesterol intermediates—particularly 7-dehydrocholesterol—that protect against ferroptosis, a cell-death vulnerability in the oxygen-rich lung. Manipulating PCSK9 experimentally redirected metastases between organs, establishing it as both necessary and sufficient for organ site preference. Patient tumor specimens confirmed these patterns clinically.
