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Quest for origin of Ewing Sarcoma successful

The left image shows the anlage of a leg with EWS / FLI1 expression in which bone should already be formed. But the stem cells fail to produce precursor cells that support a healthy bone structure (arrows, compare to image right). Copyright: Unrestricted unmodified use with reference to the copyright holder Ludwig Boltzmann Gesellschaft

In order to develop better therapies against cancer, researchers are now faced with ever-increasing efforts. Since cancer is a complex disease affecting the entire organism, genetically modified mice play an important role in cancer research. Above all in rare cancers, clinically relevant animal models are essential to investigate the effect of new drugs. For this reason, researchers have tried for many years but failed to develop a suitable model for Ewing sarcoma. The PhD student Tahereh Javaheri at the Ludwig Boltzmann Institute for Cancer Research in close cooperation with St. Anna Kinderkrebsforschung has now achieved this task. Her results have now been published in "Cell Death & Disease". The publication describes how the Oncogene EWS / FLI1 has been successfully integrated into the correct precursor cells. Thus, aggressively metastasizing tumors develop, which resemble the human disease. The clinically relevant animal model will be used in the future to advance new therapies.

James Ewing described bone tumors as a pathologist and lent his name to the sarcoma, which occurs primarily in the bones of children and adolescents. Ewing sarcoma remain today a grave disease, requiring frequently an intense therapy and surgical interventions. James Ewing founded the Memorial Sloan Kettering Cancer Center in New York, the world's oldest and one of the most famous cancer research centers globally. He was a visionary scientist and he is regarded as the pioneer of interdisciplinary cancer research, also because he pioneered animal models for cancer research. It is therefore an irony that as yet no suitable animal model has been devised for these malignant bone tumors, which are named after Ewing.

Ewing sarcoma is caused by two chromosomes breaking, which fuse to form a novel gene giving rise to an oncogenic gene product. The Ewing Sarcoma and one particular fusion gene (EWS / FLI1) has been intensively studied for several years at St. Anna Kinderkrebsforschung. Using modern genetic and molecular biology methods, it is now possible to introduce any gene and switch them on or off at the desired time in the cells of choice. But the original cell giving rise to Ewing has remained elusive, but scientists had long suspected that a bone stem cell (a precursor cell for bone and cartilage formation and other tissue) triggers this tumor. Javaheri introduced the EWS / FLI1 fusion gene into transgenic mice under the control of a promotor specific for bone stem cells. These mice had severe defects after birth, because bone and cartilage growth was blocked. A more accurate analysis revealed that the stem cells with the fusion gene are blockade in their differentiation. The activation of EWS / FLI1 is toxic to many cells, so the further direction was specified. "We initially assumed that the fusion gene in the right cells should be sufficient to trigger cancer. We thus decided to protect the EWS / FLI1 stem cells from programmed cell death," says Javaheri. The researchers thus combined the EWS / FLI1 fusion gene with a gene that prevents from cellular suicide. By blocking apoptosis, the researchers were able to protect the precursor cells of the Ewing sarcoma, which could develop with a high penetrance into tumors resembling the human Ewing sarcoma. It was thus possible to prove that the bone stem cells are indeed giving rise to Ewing sarcome. The first promissing steps to use this model to test noel therapies are already reported in the recent publication.

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