PUBLICATION
Ena/VASP-EVH1 inhibition prevents chemotaxis and metastasis by blocking the EVH1-WAVE2 interaction
- Authors
- Müller, M., Barone, M., Dinther, M.V., Motzny, K., Ren, J., Eichhorst, J., Albat, D., Chiha, S., Lehmann, M., Volkmer, R., Oschkinat, H., Schmalz, H.G., Ten Dijke, P., Kühne, R.
- ID
- ZDB-PUB-250626-14
- Date
- 2025
- Source
- Proceedings of the National Academy of Sciences of the United States of America 122: e2423512122e2423512122 (Journal)
- Registered Authors
- Keywords
- extravasation, metastasis, oncology, pharmacology, target validation
- MeSH Terms
-
- Animals
- Humans
- Cell Line, Tumor
- Cell Adhesion Molecules*/antagonists & inhibitors
- Cell Adhesion Molecules*/genetics
- Cell Adhesion Molecules*/metabolism
- Chemotaxis*/drug effects
- Neoplasm Metastasis
- Cell Movement
- DNA-Binding Proteins*/antagonists & inhibitors
- DNA-Binding Proteins*/genetics
- DNA-Binding Proteins*/metabolism
- Microfilament Proteins*/antagonists & inhibitors
- Microfilament Proteins*/genetics
- Microfilament Proteins*/metabolism
- Vasodilator-Stimulated Phosphoprotein
- Wiskott-Aldrich Syndrome Protein Family*/genetics
- Wiskott-Aldrich Syndrome Protein Family*/metabolism
- Mice
- Zebrafish
- Female
- PubMed
- 40560613 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Müller, M., Barone, M., Dinther, M.V., Motzny, K., Ren, J., Eichhorst, J., Albat, D., Chiha, S., Lehmann, M., Volkmer, R., Oschkinat, H., Schmalz, H.G., Ten Dijke, P., Kühne, R. (2025) Ena/VASP-EVH1 inhibition prevents chemotaxis and metastasis by blocking the EVH1-WAVE2 interaction. Proceedings of the National Academy of Sciences of the United States of America. 122:e2423512122e2423512122.
Abstract
Cancer therapy would benefit from suppressing cancer cell motility in the process of metastasis. Such directed cell migration relies on the propulsive force established by the filamentous actin network within lamellipodia. Proteins of the Ena/VASP family and the WAVE regulatory complex orchestrate lamellar protrusions and therefore provide promising targets for pharmacological interventions. Here, we report a cross-talk between Ena/VASP proteins and WAVE2 that is important for cancer cell extravasation. Mutating the EVH1 domain recognition motif in WAVE2 abrogates chemotaxis of triple-negative MDA-MB-231 breast cancer cells and reduces their extravasation in a zebrafish model. In pilot experiments, orthotopic implantation of these cells into mice led to a reduction in macrometastasis, resulting in prolonged survival. Similarly, intervention by an Ena/VASP-EVH1 inhibitor also reduced metastasis in vivo. Our results suggest that pharmacological interference with the Ena/VASP-WAVE2 interaction may thus reduce metastasis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping