Our aim is to understand the role of Rho GTPases and Rho GTPase effectors in vivo during development and disease
The Rho GTPases are a family of 20 genes with major roles in organizing the actin cytoskeleton as well as in other processes such as regulation of proliferation, differentiation and stemness. They are part of a complex signaling network involving a large number of effector and regulator molecules, which in turn are controlled by many different signaling pathways. Understanding how this complex Rho GTPase signaling network is functioning in vivo during development and disease is the major research question of our lab.
The Rho GTPase effector N-WASP controls skin inflammation by an epigenetic mechanism
- Nuclear N-WASP preserves H3K9 dimethylation in keratinocytes by preventing G9a/GLP degradation
- Decreased H3K9 dimethylation in keratinocytes triggers an IL-23 dependent skin inflammation
- Psoriatic skin lesions show decreased levels of H3K9 dimethylation and increased levels of IL-23
The Rho GTPase effector N-WASP is required for chemically induced skin tumor formation in mice
- Mice with a keratinocyte restricted ko of N-WASP are resistant to DMBA/TPA induced skin tumor
- N-WASP-null keratinocytes show premature senescence, corresponding with a decrease in keratinocyte stem cells in vivo
Loss of RhoA promotes skin tumor formation
- RhoA expression is decreased in head and neck squamous cancers
- Loss of RhoA promotes invasiveness of keratinocytes in a murine skin tumor model
- Increased invasiveness of RhoA-ko keratinocytes is relates to a compensatory increase in RhoB-ROCK activation
- Analysing the functional importance of alterations of Rho GTPase signaling genes in cancer
Rho GTPase signaling genes are altered in different solid cancers. Using genetically modified mice and cellular models we are trying to understand how these genetic alterations are contributing to cancer formation and progression.
- Analysing Rho GTPase signaling in the nucleus
Rho GTPase signaling is well described in the cytoplasm, but poorly understood in the nucleus. Using innovative approaches we are trying to elucidate Rho GTPase signaling in this cellular compartment.
- Analysing the role of Rho GTPase signaling in mouse development
Using genetically modified mice we investigate the role of Rho GTPase signaling genes during mouse development.
Genetically modified mice
To study in vivo function of Rho GTPases in a model system we generate and analyse genetically modified mice.
CRISPR genome editing
CRISPR genome editing is the standard technique to explore and validate gene function in primary cells and in cell lines.
Quantitative image analysis
For unbiased analysis of fluorescent stainings we establish automatic analysis pipelines using image analysis programs such as CellProfiler.
Li H, Petersen S, Garcia Mariscal A, Brakebusch C. (2019) Negative Regulation of p53-Induced Senescence by N-WASP Is Crucial for DMBA/TPA-Induced Skin Tumor Formation. Cancer Res. 2019 May 1;79(9):2167-2181.
Svensmark JH, Brakebusch C. (2019) Rho GTPases in cancer: friend or foe? Oncogene. 8:7447-7456
Ge, J, Burnier, L, Adamopoulou, M, Schaks, M, Rottner, K, Brakebusch, C (2018) RhoA, Rac1 and Cdc42 differentially regulate aSMA and collagen I expression in mesenchymal stem cells. J. Biol Chem., 293:9358-9369
Li H, Yao Q, Garcia Mariscal A, Wu X, Hülse J, Pedersen E, Helin K, Waisman A, Vinkel C, Thomsen SF, Avgustinova A, Aznar Benitah S, Lovato P, Norsgaard H, Mortensen MS, Veng L, Rozell B, Brakebusch C (2018) Epigenetic control of IL-23 expression in keratinocytes is important for chronic skin inflammation. Nat. Comm 12;9(1):1420
García-Mariscal A, Li H, PedersenE, PeyrollierK, Ryan KM, Stanley A, Quondamatteo F, Brakebusch C (2018) Loss of RhoA promotes skin tumor formation and invasion by upregulation of RhoB. Oncogene, 37: 847-860
IMGENE is a European CRISPR genome editing training network devoted to educating the next generation of European researchers in the field of CRIPSR genome editing technology. Aim of IMGENE is to improve CRISPR genome editing
PathBio is an ERASMUS+ Knowledge Alliance consortium from across the globe to cooperate on pooling resources and expertise in order to build the framework for a European post graduate degree in Precision pathobiology for disease models.