An allosteric inhibitor of RhoGAP class-IX myosins suppresses the metastatic features of cancer cells

verfasst von

Despoina Kyriazi, Lea Voth, Almke Bader, Wiebke Ewert, Juliane Gerlach, Kerstin Elfrink, Peter Franz, Mariana I. Tsap, Bastian Schirmer, Julia Damiano-Guercio, Falk K. Hartmann, Masina Plenge, Azam Salari, Dennis Schöttelndreier, Katharina Strienke, Nadine Bresch, Claudio Salinas, Herwig O. Gutzeit, Nora Schaumann, Kais Hussein, Heike Bähre, Inga Brüsch, Peter Claus, Detlef Neumann, Manuel H. Taft, Halyna R. Shcherbata, Anaclet Ngezahayo, Martin Bähler, Mahdi Amiri, Hans Joachim Knölker, Matthias Preller, Georgios Tsiavaliaris

Abstract

Aberrant Ras homologous (Rho) GTPase signalling is a major driver of cancer metastasis, and GTPase-activating proteins (GAPs), the negative regulators of RhoGTPases, are considered promising targets for suppressing metastasis, yet drug discovery efforts have remained elusive. Here, we report the identification and characterization of adhibin, a synthetic allosteric inhibitor of RhoGAP class-IX myosins that abrogates ATPase and motor function, suppressing RhoGTPase-mediated modes of cancer cell metastasis. In human and murine adenocarcinoma and melanoma cell models, including three-dimensional spheroid cultures, we reveal anti-migratory and anti-adhesive properties of adhibin that originate from local disturbances in RhoA/ROCK-regulated signalling, affecting actin-dynamics and actomyosin-based cell-contractility. Adhibin blocks membrane protrusion formation, disturbs remodelling of cell-matrix adhesions, affects contractile ring formation, and disrupts epithelial junction stability; processes severely impairing single/collective cell migration and cytokinesis. Combined with the non-toxic, non-pathological signatures of adhibin validated in organoids, mouse and Drosophila models, this mechanism of action provides the basis for developing anti-metastatic cancer therapies.

Organisationseinheit(en)

Institut für Zellbiologie und Biophysik
Abteilung Zellphysiologie und Biophysik

Externe Organisation(en)

Medizinische Hochschule Hannover (MHH)
Hochschule Bonn-Rhein-Sieg (H-BRS)
Technische Universität Dresden
Westfälische Wilhelms-Universität Münster (WWU)
Nordstadt Krankenhaus
SMATHERIA gGmbH

Typ

Artikel

Journal

Nature Communications

Band

15

Anzahl der Seiten

25

ISSN

2041-1723

Publikationsdatum

16.11.2024

Publikationsstatus

Veröffentlicht

Peer-reviewed

Ja

ASJC Scopus Sachgebiete

Allgemeine Chemie, Allgemeine Biochemie, Genetik und Molekularbiologie, Allgemeine Physik und Astronomie

Ziele für nachhaltige Entwicklung

SDG 3 – Gute Gesundheit und Wohlergehen

Elektronische Version(en)

https://doi.org/10.1038/s41467-024-54181-6 (Zugang: Offen)