The liver talks back: NPY orchestrates attraction of cancer cells and CHK2-dependent clonogenicity in the metastatic niche
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 TGFβ, 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (38)
Laura Wormser
Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg
Valerie Fritz
Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg
Melanie Kappelmann-Fenzl
Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg
Nicole Rachinger
Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg
Pol Escudé
Central Diagnostic Laboratory Research, University Medical Center Utrecht
Karin Enderle
Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg
Matthias D. Kaufmann
Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg
Miriam Düll
Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg
Abdo Mahli
Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg
Sebastian Zundler
Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg
Moritz Leppkes
Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg
Stefan Fischer
Faculty of Computer Science, Deggendorf Institute of Technology
Felix Elsner
Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg
Carol-Immanuel Geppert
Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg
Michael Hannus
Biochemistry Center Regensburg, Laboratory for RNA Biology, University of Regensburg, siTools Biotech GmbH
Susanne Merkel
Department of Surgery, University of Erlangen-Nürnberg
Michael Erdmann
Department of Dermatology, Uniklinikum Erlangen, Friedrich Alexander University
Claudia Günther
Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg
Katja Evert
Institute of Pathology, University of Regensburg
Zubeir El Ahmad
Faculty of Computer Science, Deggendorf Institute of Technology
Gunter Meister
Biochemistry Center Regensburg, Laboratory for RNA Biology, University of Regensburg
Elisabetta D’Avanzo
Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander
Marc P. Stemmler
Clemens Neufert
Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg
Andreas E. Kremer
Department of Gastroenterology and Hepatology, University Hospital Zürich, University of Zürich
Georg F. Weber
Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen
Thomas Brabletz
Stephan von Hörsten
Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen
Reiner Wiest
Department of Visceral Surgery and Medicine, University Inselspital
Raymond Schiffelers
Central Diagnostic Laboratory Research, University Medical Center Utrecht
Arndt Hartmann
Deutsches Zentrum für Immuntherapie, Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen
Jürgen Siebler
Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg
Jonel Trebicka
Department of Internal Medicine B, University of Münster
Maximilian Waldner
Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg
Markus F. Neurath
Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg
Claus Hellerbrand
Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg
Anja K. Bosserhoff
Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg
Peter Dietrich
Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nürnberg