We are interested in cellular signaling transduction and its role in cell homeostasis, differentiation and disease. During development and homeostasis, cells constantly receive signals that determine whether they divide, differentiate or die. Inappropriate control of signaling has been linked with many diseases and is frequently associated with cancer. We study principle mechanisms of signaling pathways how they are dysregulated in cancer by high-throughput functional genomic approaches.

Wnt signaling in cancer and development

Wnt signaling are an evolutionarily conserved signal transduction route that plays key roles during development, stem cell maintenance and human diseases. Aberrant activation of the Wnt signaling, for example, has been linked to the development of colorectal cancer. Mutations that inactivate the APC tumour suppressor gene are found in 80-90% of all colon cancers. Similarly, activating mutations in other Wnt pathway components have been found in hepatocarcinomas and many other tumors. We work on identifying and characterizing novel Wnt pathway components using genetic and genomic approaches in order to understand how Wnt signaling is regulated under normal and pathophysiological conditions. In the past years, a particular focus of our studies have been on systematic screening approaches, novel routes how Wnt proteins are secreted and how signals are transmitted at the plasma membrane.

Systems Genetics

Genes display epistatic (genetic) interactions, whereby the presence of one genetic variant can mask, alleviate or amplify the phenotypic effect of other variants. Genetic interactions have been shown to have profound effects during normal development and in disease. Two genes show a genetic interaction if the phenotype of allele combinations (or double perturbations) is different from the expected combination of the individual phenotypes. Genetic interactions occur, for example, when a cellular process is controlled by two parallel pathways: loss of gene products in one pathway are buffered, and only when the both pathways are disturbed, a phenotype is observed. Conversely, the phenotype of closely collaborating proteins, for example, in a protein complex, is often not further enhanced when more than one of its gene products are depleted. We use high-throughput reverse genetic approaches in cells to comprehensively map genetic interaction in normal and cancer cells.

High-throughput biology and technology development

We develop technologies for high-throughput screening in cultured cells and bioinformatic methods to analyze large phenotypic data sets, including the development of miniaturized assay formats, new approaches for massively parallel perturbation analysis and phenotyping by deep-sequencing.

Genome engineering

We develop novel experimental approaches using CRISPR/Cas9 mediated genome-engineering to study effect of genetic variants on cellular signaling. We also develop computational methods for the design of libraries that facilitate CRISPR/Cas9-mediated knock-out screens.

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