Relevance of regulator proteins of actin remodeling for the gain of an invasive phenotype in Ewing's sarcoma

• Applicant: Professor Dr. Konrad Steinestel
• Subject Area: Pathology ; Hematology, Oncology ; Cell Biology
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 277965366

The overall aim of the project is to analyze the role of protein regulators of actin reorganization (nucleation-promoting factors, NPFs) that have been shown to be of key relevance for the formation of specialized cellular protrusions and invasion of epithelial tumors, in Ewing's sarcoma. With this approach, we plan to identify potential pharmacological targets for antiinvasive therapies.The following three subgoals were defined:1. Analysis of the expression patterns of key regulators of actin reorganization in Ewing's sarcoma with regard to clinical data from the EWING 2008 trial of the international cooperative Ewing Sarcoma Study Centre, Münster.2. Analysis of the dynamics of specialized cellular protrusions (invadopodia, lamellipodia) and their regulation through intracellular signaling circuits (with special emphasis on the EWS/FLI transformation by the use of an established knockout model) as well as the subcellular localization and interaction between different NPFs; impact of these factors on migration and invasion in vitro3. Possibilities of pharmacological interference with NPFs and their impact on cell morphology, dynamics of specialized cellular protrusions and subcellular localization of NPFs and their interactions among each other; impact on migration and invasion in vitro and in vivoThese subgoals do not strictly build up on each other, but rather contribute in a modular way to the further characterization of the way how Ewing's sarcoma cells metastasize. For example, EWS/FLI knockdown as well as pharmacological interference (subgoals 2 and 3) might help to identify additional targets that might then be further characterized according to step 1.

• DFG Programme: Research Grants
• Co-Investigators: Professorin Dr. Uta Dirksen; Professor Dr. Wolfgang Hartmann