The liver talks back: NPY orchestrates attraction of cancer cells and CHK2-dependent clonogenicity in the metastatic niche

Wormser L, Fritz V, Kappelmann-Fenzl M, Rachinger N, Escudé P, Enderle K, Kaufmann M, Düll M, Mahli A, Zundler S, Leppkes M, Fischer S, Elsner F, Geppert CI, Hannus M, Merkel S, Erdmann M, Günther C, Evert K, El Ahmad Z, Meister G, D'Avanzo E, Stemmler M, Neufert C, Kremer AE, Weber GF, Brabletz T, von Hörsten S, Wiest R, Schiffelers R, Hartmann A, Siebler J, Trebicka J, Waldner M, Neurath M, Hellerbrand C, Boßerhoff AK, Dietrich P (2025)

Publication Type: Journal article

Publication year: 2025

Journal

Proceedings of the National Academy of Sciences of the United States of America National Academy of Sciences

Book Volume: 122

Pages Range: e2518418122

Journal Issue: 47

DOI: 10.1073/pnas.2518418122

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.

Authors with CRIS profile

Laura Wormser Lehrstuhl für Biochemie und Molekulare Medizin Valerie Fritz Lehrstuhl für Biochemie und Molekulare Medizin Melanie Kappelmann-Fenzl Lehrstuhl für Biochemie und Molekulare Medizin Nicole Rachinger Lehrstuhl für Biochemie und Molekulare Medizin Matthias Kaufmann Department of Dermatology Miriam Düll Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Abdo Mahli Lehrstuhl für Biochemie und Molekulare Medizin Sebastian Zundler Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Moritz Leppkes Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Felix Elsner Institute of Pathology Carol-Immanuel Geppert Institute of Pathology Susanne Merkel Department of Surgery Claudia Günther Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Elisabetta D'Avanzo Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Marc Stemmler Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Clemens Neufert Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Thomas Brabletz Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Stephan von Hörsten Professur für Experimentelle Biomedizin Jürgen Siebler Professur für Hepatologie Maximilian Waldner Professur für Funktionelle Bildgebung in der Medizin Markus Neurath Lehrstuhl für Innere Medizin I (Medizin 1) Claus Hellerbrand Professur für Biochemie und Molekulare Pathobiologie Anja Katrin Boßerhoff Lehrstuhl für Biochemie und Molekulare Medizin Peter Dietrich Lehrstuhl für Biochemie und Molekulare Medizin

Involved external institutions

Technische Hochschule Deggendorf DE Germany (DE) Universität Regensburg DE Germany (DE) University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) Inselspital, Universitätsspital Bern CH Switzerland (CH) Westfälische Wilhelms-Universität (WWU) Münster DE Germany (DE) Universitätsspital Zürich (USZ) CH Switzerland (CH)

How to cite

APA:

Wormser, L., Fritz, V., Kappelmann-Fenzl, M., Rachinger, N., Escudé, P., Enderle, K.,... Dietrich, P. (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), e2518418122. https://doi.org/10.1073/pnas.2518418122

MLA:

Wormser, Laura, et al. "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 (2025): e2518418122.

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