PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer

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 and Rushika M. Perera ()
Additional contact information
Gilles Rademaker: University of California San Francisco
Grace A. Hernandez: University of California San Francisco
Yurim Seo: University of California San Francisco
Sumena Dahal: University of California San Francisco
Lisa Miller-Phillips: University of California
Alexander L. Li: University of California San Francisco
Xianlu Laura Peng: University of North Carolina at Chapel Hill
Changfei Luan: University of North Carolina at Chapel Hill
Longhui Qiu: University of California San Francisco
Maude A. Liegeois: University of California San Francisco
Bruce Wang: University of California
Kwun W. Wen: University of California San Francisco
Grace E. Kim: University of California San Francisco
Eric A. Collisson: Fred Hutchinson Cancer Research Center
Stephan F. Kruger: University of Munich Comprehensive Cancer Center
Stefan Boeck: University of Munich Comprehensive Cancer Center
Steffen Ormanns: Medical University Innsbruck
Michael Guenther: Medical University Innsbruck
Volker Heinemann: University of Munich Comprehensive Cancer Center
Michael Haas: University of Munich Comprehensive Cancer Center
Mark R. Looney: University of California San Francisco
Jen Jen Yeh: University of North Carolina at Chapel Hill
Roberto Zoncu: University of California Berkeley
Rushika M. Perera: University of California San Francisco

Nature, 2025, vol. 643, issue 8074, 1381-1390

Abstract: Abstract To grow at distant sites, metastatic cells must overcome major challenges posed by the unique cellular and metabolic composition of secondary organs1. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that metastasizes to the liver and lungs. Despite evidence of metabolic reprogramming away from the primary site, the key drivers that dictate the ability of PDAC cells to colonize the liver or lungs and survive there remain undefined. Here we identified PCSK9 as predictive of liver versus lung colonization by integrating metastatic tropism data of human PDAC cell lines2, in vivo metastasis modelling in mice and gene expression correlation analysis. PCSK9 negatively regulates low density lipoprotein (LDL)-cholesterol import and, accordingly, PCSK9-low PDAC cells preferentially colonize LDL-rich liver tissue. LDL-cholesterol taken up by liver-avid PCSK9-low cells supports activation of pro-growth mTORC1 activation at the lysosome, and through conversion into the signalling oxysterol, 24(S)-hydroxycholesterol, reprogrammes the microenvironment to release nutrients from neighbouring hepatocytes. Conversely, PCSK9-high, lung-avid PDAC cells rely on transcriptional upregulation of the distal cholesterol synthesis pathway to generate intermediates—7-dehydrocholesterol and 7-dehydrodesmosterol—with protective action against ferroptosis, a vulnerability in the oxygen-rich microenvironment of the lung. Increasing the amount of PCSK9 redirected liver-avid cells to the lung whereas ablating PCSK9 drove lung-avid cells to the liver, thereby establishing PCSK9 as necessary and sufficient for secondary organ site preference. Our studies reveal PCSK9-driven differential utilization of the distal cholesterol synthesis pathway as a key and potentially actionable driver of metastatic growth in PDAC.

Date: 2025
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DOI: 10.1038/s41586-025-09017-8

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