Wormser, Laura and Fritz, Valerie and Kappelmann-Fenzl, Melanie and Rachinger, Nicole and Escude, Pol and Enderle, Karin and Kaufmann, Matthias D. and Dull, Miriam and Mahli, Abdo and Zundler, Sebastian and Leppkes, Moritz and Fischer, Stefan and Elsner, Felix and Geppert, Carol-Immanuel and Hannus, Michael and Merkel, Susanne and Erdmann, Michael and Gunther, Claudia and Evert, Katja and El Ahmad, Zubeir and Meister, Gunter and D'Avanzo, Elisabetta and Stemmler, Marc P. and Neufert, Clemens and Kremer, Andreas E. and Weber, Georg F. and Brabletz, Thomas and von Horsten, Stephan and Wiest, Reiner and Schiffelers, Raymond and Hartmann, Arndt and Siebler, Jurgen and Trebicka, Jonel and Waldner, Maximilian and Neurath, Markus F. and Hellerbrand, Claus and Bosserhoff, Anja K. and Dietrich, Peter (2025) The liver talks back: NPY orchestrates attraction of cancer cells and CHK2-dependent clonogenicity in the metastatic niche. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 122 (47): e251841812. ISSN 0027-8424, 1091-6490
Full text not available from this repository. (Request a copy)Abstract
RNA interference (RNAi) therapeutics represent breakthrough discoveries, but their use in cancer remains limited due to hepatocyte-specific targeting. Cancer metastasis is regulated by complex crosstalk between tumor cells and niche-derived factors. However, the molecular mechanisms enabling metastatic seeding and outgrowth in the liver remain incompletely understood, representing a major clinical challenge. We identified neuropeptide Y (NPY) as a promotor of liver metastasis. Hepatocyte-derived NPY attracts metastatic tumor cells to the liver niche. Subsequent microenvironment activation induces TGF(3, promoting a vicious cycle of perimetastatic NPY secretion and liver metastasis. Concomitantly, cancer cells upregulate the NPY-5 receptor (Y5R) which is correlated with liver metastasis. NPY-Y5R crosstalk drives chemotactic migration via cAMP and ERK signaling. Moreover, NPY-Y5R activation dephosphorylates checkpoint kinase 2 to promote clonogenicity and proliferation of cancer cells. Lipid nanoparticles (LNPs) are a promising drug delivery vehicle for siRNAs. LNPs carrying siRNA pools targeting NPY were designed, and preclinical studies provided evidence for efficacy for the treatment of liver metastasis. Our findings transform the limitation of hepatocyte specificity of RNA interference into a therapeutic advantage, introducing a paradigm for the treatment of hepatic metastases.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | NEUROPEPTIDE-Y; MUCOSAL MELANOMA; MIGRATION; KINASE; metastasis; metastatic niche; NPY; liver metastasis; cancer |
| Subjects: | 500 Science > 570 Life sciences 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie Biology, Preclinical Medicine > Institut für Biochemie, Genetik und Mikrobiologie > Lehrstuhl für Biochemie I > Prof. Dr. Gunter Meister |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Jun 2026 11:55 |
| Last Modified: | 02 Jun 2026 11:55 |
| URI: | https://pred.uni-regensburg.de/id/eprint/67379 |
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