Die Funktion des Linker of Nucleoskeleton and Cytoskeleton (LINC)-Komplexes und nukleärer Aktin-Polymerisation in der Myocardin Related Transcription Factor A (MRTF-A) regulierten Tumorzellinvasion

To what extent nuclear actin polymerization is involved in tumor cell inva-sion is not yet known and this doctoral thesis aimed to study that question. Furthermore a possible mechanosensitive function for the Linker of Nu-cleoskeleton and Cytoskeleton (LINC)-Complex at the nuclear membrane and a specific involvement of Myocardin Related Transcription Factor A (MRTF-A) were investigated in this context. A postulated pathway be-tween cell membrane anchored Integrins and the nuclear actin fraction was of special interest, as an integration of extracellular signaling might be possible that way. In order to assess these questions a number of cell biological methods were used. The invasive behaviour of human fibrosarcoma cells (HT1080) was studied in a novel invasion assay which was established to quantitively and qualitatively study invading cells and their subcellular structures in realtime. Different means of disrupting nuclear actin polymerization and the integrity of the LINC complex were used to investigate their possible functional implications in invasion. Studying nuclear actin filaments was made possible by using methods of endogenous nuclear actin colorization, allowing for differential visualization of live and endogenous filaments un-der various conditions in active tumor cell invasion. For the first time nuclear actin filaments and the shuttling of MRTF-A-GFP were observed in invading HT1080 cells and in stationary cells using Fi-bronectin stimulation. Through use of quantitative studies a significant im-portance was shown for nuclear actin polymerization and the LINC-complex in efficient collagen matrix invasion. Putting together these ob-servations, the description of an Integrin-LINC-nuclear-actin-MRTF-A pathway in tumor cell invasion can be proposed. This signaling pathway possibly integrates extracellular information and mechanical signals. It in-teracts with the actin cytoskeleton and is of importance for an efficient collagen matrix invasion. The description of this pathway opens up new possibilites in researching the interaction of invading tumor cells with the extracellular matrix and allows further investigations for possible new pharmacological targets in cancer therapy.