Background: Ewing sarcoma is a malignancy of primitive cells, possibly of mesenchymal origin. It is probable that genetic perturbations other than EWS-FLI1 cooperate with it to produce the tumor. Sequencing studies identified STAG2 mutations in approximately 15% of cases in humans. In the present study, we hypothesize that loss of Stag2 cooperates with EWS-FLI1 in generating sarcomas derived from murine mesenchymal stem cells (MSCs). Methods: Mice bearing an inducible EWS-FLI1 transgene were crossed to p53 -/- mice in pure C57/Bl6 background. MSCs were derived from the bone marrow of the mice. EWS-FLI1 induction and Stag2 knockdown were achieved in vitro by adenovirus-Cre and shRNA-bearing pGIPZ lentiviral infection, respectively. The cells were then treated with ionizing radiation to 10 Gy. Anchorage independent growth in vitro was assessed by soft agar assays. Cellular migration and invasion were evaluated by transwell assays. Cells were injected with Matrigel intramuscularly into C57/Bl6 mice to test for tumor formation. Results: Primary murine MSCs with the genotype EWS-FLI1 p53 -/- were resistant to transformation and did not form tumors in syngeneic mice without irradiation. Stag2 inhibition increased the efficiency and speed of sarcoma formation significantly in irradiated EWS-FLI1 p53 -/- MSCs. The efficiency of tumor formation was 91% for cells in mice injected with Stag2-repressed cells and 22% for mice receiving cells without Stag2 inhibition (p
CITATION STYLE
El Beaino, M., Liu, J., Wasylishen, A. R., Pourebrahim, R., Migut, A., Bessellieu, B. J., … Lin, P. P. (2020). Loss of Stag2 cooperates with EWS-FLI1 to transform murine Mesenchymal stem cells. BMC Cancer, 20(1). https://doi.org/10.1186/s12885-019-6465-8
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