2. Academic Validation
  3. PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer

PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer

  • Nature. 2025 May 21. doi: 10.1038/s41586-025-09017-8.
Gilles Rademaker 1 2,  Grace A Hernandez 1 2,  Yurim Seo 3,  Sumena Dahal 1 2,  Lisa Miller-Phillips 2 4,  Alexander L Li 1,  Xianlu Laura Peng 5,  Changfei Luan 5,  Longhui Qiu 3,  Maude A Liegeois 6,  Bruce Wang 2 7,  Kwun W Wen 8,  Grace E Kim 8,  Eric A Collisson 9,  Stephan F Kruger 4,  Stefan Boeck 4 10 11,  Steffen Ormanns 12 13,  Michael Guenther 12 13,  Volker Heinemann 4,  Michael Haas 4 10,  Mark R Looney 3,  Jen Jen Yeh 5 14,  Roberto Zoncu 15,  Rushika M Perera 16 17 18
Affiliations

Affiliations

  • 1 Department of Anatomy, University of California San Francisco, San Francisco, CA, USA.
  • 2 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
  • 3 Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
  • 4 Department of Hematology/Oncology, LMU Klinikum, University of Munich Comprehensive Cancer Center, Munich, Germany.
  • 5 Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 6 Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
  • 7 Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
  • 8 Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
  • 9 Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • 10 Department of Hematology and Oncology, München Klinik Neuperlach, Munich, Germany.
  • 11 German Cancer Consortium (DKTK), Munich, Germany.
  • 12 Institute of General Pathology, Medical University Innsbruck, Innsbruck, Austria.
  • 13 Innpath Institute for Pathology, Tirol Kliniken, Innsbruck, Austria.
  • 14 Departments of Surgery and Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
  • 15 Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, USA.
  • 16 Department of Anatomy, University of California San Francisco, San Francisco, CA, USA. rushika.perera@ucsf.edu.
  • 17 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA. rushika.perera@ucsf.edu.
  • 18 Department of Pathology, University of California San Francisco, San Francisco, CA, USA. rushika.perera@ucsf.edu.
PMID: 40399683 DOI: 10.1038/s41586-025-09017-8
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.

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