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Insight into the Etiology of Undifferentiated Soft Tissue Sarcomas from a Novel Mouse Model


Fleming JT , Brignola E , Chen L , Guo Y , Zhao S , Wang Q , Li B , Correa H , Ermilov AN , Dlugosz AA , Chiang C , . Molecular cancer research : MCR. 2019 1 25; ().


Aberrant activation of the Hedgehog signaling pathway has been linked to the formation of numerous cancer types, including the myogenic soft tissue sarcoma, embryonal rhabdomyosarcoma (eRMS). Here, we report , a novel mouse model in which human GLI2A, a constitutive activator of Hedgehog signaling, induced undifferentiated sarcomas that were phenotypically divergent from eRMS. Rather, sarcomas arising in mice featured some characteristics that were reminiscent of Ewing sarcoma. Even though it is widely understood that Ewing sarcoma formation is driven by gene fusions, a genetically defined mouse model is not well-established. While gene fusions were not present in sarcomas, precluding their designation as Ewing sarcoma, we did find that GLI2A induced expression of known gene targets essential to Ewing pathogenesis, most notably, Moreover, we found that naïve mesenchymal progenitors originate tumors in mice. Altogether, our work provides a novel genetic mouse model, which directly connects oncogenic Hedgehog activity to the etiology of undifferentiated soft tissue sarcomas for the first time. The finding that activation of Gli2 transcription factor is sufficient to induce Ewing-like sarcomas provides a direct transformative role of the Hedgehog signaling pathway in undifferentiated soft tissue sarcoma.