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@ARTICLE{Rademaker:301517,
      author       = {G. Rademaker and G. A. Hernandez and Y. Seo and S. Dahal
                      and L. Miller-Phillips and A. L. Li and X. L. Peng and C.
                      Luan and L. Qiu and M. A. Liegeois and B. Wang and K. W. Wen
                      and G. E. Kim and E. A. Collisson and S. F. Kruger and S.
                      Boeck$^*$ and S. Ormanns and M. Guenther and V. Heinemann
                      and M. Haas and M. R. Looney and J. J. Yeh and R. Zoncu and
                      R. M. Perera},
      title        = {{PCSK}9 drives sterol-dependent metastatic organ choice in
                      pancreatic cancer.},
      journal      = {Nature},
      volume       = {643},
      number       = {8074},
      issn         = {0028-0836},
      address      = {London [u.a.]},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2025-01054},
      pages        = {1381-1390},
      year         = {2025},
      note         = {2025 Jul;643(8074):1381-1390},
      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.},
      cin          = {MU01},
      ddc          = {500},
      cid          = {I:(DE-He78)MU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40399683},
      doi          = {10.1038/s41586-025-09017-8},
      url          = {https://inrepo02.dkfz.de/record/301517},
}