PCSK9 drives sterol-dependent metastatic organ choice in pancreatic cancer

• 成果类型: Article
• 署名作者: Rademaker, Gilles; Hernandez, Grace A.; Seo, Yurim; Dahal, Sumena; Miller-Phillips, Lisa; Li, Alexander L.; Peng, Xianlu Laura; Luan, Changfei; Qiu, Longhui; Liegeois, Maude A.; Wang, Bruce; Wen, Kwun W.; Kim, Grace E.; Collisson, Eric A.; Kruger, Stephan F.; Boeck, Stefan; Ormanns, Steffen; Guenther, Michael; Heinemann, Volker; Haas, Michael; Looney, Mark R.; Yeh, Jen Jen; Zoncu, Roberto; Perera, Rushika M.
• 署名单位: University of California System; University of California San Francisco; University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of California System; University of California San Francisco; University of Munich; University of North Carolina; University of North Carolina Chapel Hill; University of California System; University of California San Francisco; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Fred Hutchinson Cancer Center; Helmholtz Association; German Cancer Research Center (DKFZ); Medical University of Innsbruck; University of North Carolina; University of North Carolina Chapel Hill; University of North Carolina; University of North Carolina Chapel Hill; University of California System; University of California Berkeley
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2832
• DOI: 10.1038/s41586-025-09017-8
• 发表日期: 2025-07-31
• 关键词: ductal adenocarcinoma; pulmonary metastases; cholesterol; subtypes; tumor; microenvironment; progression; mechanisms; PATHWAY; brain

摘要

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.