Study Unveils Protein That May Be Responsible for Spread of Pancreatic Cancer

A protein called PCSK9 determines how pancreatic cancer cells metastasize to different parts of the body especially the lungs or liver. The findings are published in Nature.

The spread of cancer cells to organs like these often produces the very first symptoms of pancreatic cancer. But by that time, the pancreatic cancer has spread out of control.

Researchers analyzed data from MetMap, a project at the Broad Institute, an independent research organization, to find pancreatic cancer cell lines that had a tendency to colonize either the lung or the liver. Then, they looked for genomic differences that could reveal why, or even how, these cells preferred one organ over the other.

Their analysis turned up a protein called PCSK9 that controls how cells obtain cholesterol. When PCSK9 levels are low, pancreatic cancer cells consume nearby cholesterol, which is abundant in the liver. When PCSK9 levels are high, the cancer cells produce their own cholesterol.

They also make molecules that protect them from damage by oxygen, a perfect adaptation to survival in the lungs. When the team forced pancreatic cancer cells that were destined for the liver to express PCSK9, the cells made a detour to the lungs.

"Cancers persist by adapting to live in new tissues and organs, and we found that pancreatic tumors use PCSK9 to adapt as they spread," said Rushika Perera, PhD, the Deborah Cowan Endowed Associate Professor of Anatomy at UCSF and senior author of the paper. "It opens the door to fighting metastatic cancer growth by manipulating how cells acquire their cholesterol.

Reference: Gilles Rademaker, Grace A. Hernandez, Yurim Seo, Sumena Dahal, Lisa Miller-Phillips, Alexander L. Li, Xianlu Laura Peng, Changfei Luan, Longhui Qiu, Maude A. Liegeois, Bruce Wang, Kwun W. Wen, Grace E. Kim, Eric A. Collisson, Stephan F. Kruger, Stefan Boeck, Steffen Ormanns, Michael Guenther, Volker Heinemann, Michael Haas, Mark R. Looney, Jen Jen Yeh, Roberto Zoncu, Rushika M. Perera. PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer. Nature, 2025; DOI: 10.1038/s41586-025-09017-8