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

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 and Georgios Tsiavaliaris ()
Additional contact information
Despoina Kyriazi: Hannover Medical School
Lea Voth: Hannover Medical School
Almke Bader: Hannover Medical School
Wiebke Ewert: Hannover Medical School
Juliane Gerlach: TU Dresden
Kerstin Elfrink: University of Münster
Peter Franz: Hannover Medical School
Mariana I. Tsap: Hannover Medical School
Bastian Schirmer: Hannover Medical School
Julia Damiano-Guercio: Hannover Medical School
Falk K. Hartmann: Hannover Medical School
Masina Plenge: Leibniz Universität Hannover
Azam Salari: Hannover Medical School
Dennis Schöttelndreier: Hannover Medical School
Katharina Strienke: Hannover Medical School
Nadine Bresch: Hannover Medical School
Claudio Salinas: Hannover Medical School
Herwig O. Gutzeit: TU Dresden
Nora Schaumann: Hannover Medical School
Kais Hussein: KRH Klinikum Nordstadt
Heike Bähre: Hannover Medical School
Inga Brüsch: Hannover Medical School
Peter Claus: SMATHERIA gGmbH—Non-Profit Biomedical Research Institute
Detlef Neumann: Hannover Medical School
Manuel H. Taft: Hannover Medical School
Halyna R. Shcherbata: Hannover Medical School
Anaclet Ngezahayo: Leibniz Universität Hannover
Martin Bähler: University of Münster
Mahdi Amiri: Hannover Medical School
Hans-Joachim Knölker: TU Dresden
Matthias Preller: Hannover Medical School
Georgios Tsiavaliaris: Hannover Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-25

Abstract: 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.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-54181-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54181-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-54181-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().