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

authored by

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.

Organisation(s)

Institute of Cell Biology and Biophysics
Department of Cell Physiology and Biophysics

External Organisation(s)

Hannover Medical School (MHH)
Hochschule Bonn-Rhein-Sieg
Technische Universität Dresden
University of Münster
Nordstadt Krankenhaus
SMATHERIA gGmbH

Type

Article

Journal

Nature Communications

Volume

15

No. of pages

25

ISSN

2041-1723

Publication date

16.11.2024

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

General Chemistry, General Biochemistry,Genetics and Molecular Biology, General Physics and Astronomy

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1038/s41467-024-54181-6 (Access: Open)