[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Rademaker, Gilles ; Université de Liège - ULiège > GIGA > GIGA Cancer - Metastases Research Laboratory ; Department of Anatomy, University of California San Francisco, San Francisco, CA, USA ; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
Hernandez, Grace A; Department of Anatomy, University of California San Francisco, San Francisco, CA, USA ; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
Seo, Yurim ; Department of Medicine, University of California San Francisco, San Francisco, CA, USA
Dahal, Sumena; Department of Anatomy, University of California San Francisco, San Francisco, CA, USA ; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
Miller-Phillips, Lisa; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA ; Department of Hematology/Oncology, LMU Klinikum, University of Munich Comprehensive Cancer Center, Munich, Germany
Li, Alexander L ; Department of Anatomy, University of California San Francisco, San Francisco, CA, USA
Peng, Xianlu Laura; Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Luan, Changfei; Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Qiu, Longhui; Department of Medicine, University of California San Francisco, San Francisco, CA, USA
Liégeois, Maude ; Université de Liège - ULiège > Département des sciences fonctionnelles (DSF) > Physiologie générale et des systèmes ; Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA
Wang, Bruce ; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA ; Division of Gastroenterology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
Wen, Kwun W; Department of Pathology, University of California San Francisco, San Francisco, CA, USA
Kim, Grace E ; Department of Pathology, University of California San Francisco, San Francisco, CA, USA
Collisson, Eric A ; Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Kruger, Stephan F; Department of Hematology/Oncology, LMU Klinikum, University of Munich Comprehensive Cancer Center, Munich, Germany
Boeck, Stefan ; Department of Hematology/Oncology, LMU Klinikum, University of Munich Comprehensive Cancer Center, Munich, Germany ; Department of Hematology and Oncology, München Klinik Neuperlach, Munich, Germany ; German Cancer Consortium (DKTK), Munich, Germany
Ormanns, Steffen; Institute of General Pathology, Medical University Innsbruck, Innsbruck, Austria ; Innpath Institute for Pathology, Tirol Kliniken, Innsbruck, Austria
Guenther, Michael; Institute of General Pathology, Medical University Innsbruck, Innsbruck, Austria ; Innpath Institute for Pathology, Tirol Kliniken, Innsbruck, Austria
Heinemann, Volker; Department of Hematology/Oncology, LMU Klinikum, University of Munich Comprehensive Cancer Center, Munich, Germany
Haas, Michael; Department of Hematology/Oncology, LMU Klinikum, University of Munich Comprehensive Cancer Center, Munich, Germany ; Department of Hematology and Oncology, München Klinik Neuperlach, Munich, Germany
Looney, Mark R ; Department of Medicine, University of California San Francisco, San Francisco, CA, USA
Yeh, Jen Jen; Department of Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA ; Departments of Surgery and Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Zoncu, Roberto ; Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA, USA
Perera, Rushika M ; Department of Anatomy, University of California San Francisco, San Francisco, CA, USA. rushika.perera@ucsf.edu ; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA. rushika.perera@ucsf.edu ; Department of Pathology, University of California San Francisco, San Francisco, CA, USA. rushika.perera@ucsf.edu
This work was supported by a BAEF (Belgian American Education Foundation) fellowship, Fonds L\u00E9on Fredericq, Rotary and Wallonie Bruxelles International grants (G.R.); a National Science Foundation Graduate Research Fellowship (NSF2034836) (G.A.H.); NHLBI R35 HL161241 and the Nina Ireland Program for Lung Heath (M.R.L.); National Cancer Institute R01CA260205 (R.Z.); National Cancer Institute R01CA240603 and R01CA260249, the Ed Marra Passion to Win Fund, the Weston Havens Fund and the AACR-MPM Transformative Cancer Research Award (R.M.P.); National Cancer Institute R01CA199064 (J.J.Y.), U01CA274298, P50CA257911 and U24CA211000 (X.L.P. and J.J.Y.); 7R01CA260860 and 7R01CA256969 (E.A.C.); Sky Foundation fellowship (L.M.P.); and National Institute of Diabetes and Digestive and Kidney Diseases R01DK131227 and P30DK026743 (B.W.). The authors thank the UCSF Parnassus Flow CoLab, RRID:SCR_018206 for assistance with flow cytometry and the UCSF Liver Center, supported by P30DK026743, for assistance with hepatocyte isolation.
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