Insight into the etiology of undifferentiated soft tissue sarcomas from a novel mouse model.

Aberrant activation of the Hedgehog (Hh) signaling pathway has been linked to the formation of numerous cancer types, including the myogenic soft tissue sarcoma, embryonal rhabdomyosarcoma (eRMS). Here, we report PCG2, a novel mouse model in which human GLI2A, a constitutive activator of Hh signaling, induced undifferentiated sarcomas that were phenotypically divergent from eRMS. Rather, sarcomas arising in PCG2 mice featured some characteristics that were reminiscent of Ewing sarcoma (ES). Even though it is widely understood that ES formation is driven by EWS-ETS gene fusions, a genetically-defined mouse model is not well-established. While EWS-ETS gene fusions were not present in PCG2 sarcomas, precluding their designation as ES, we did find that GLI2A induced expression of known EWS-ETS gene targets essential to Ewing pathogenesis, most notably, Nkx2.2. Moreover, we found that naive mesenchymal progenitors originate tumors in PCG2 mice. Altogether, our work provides a novel genetic mouse model, which directly connects oncogenic Hh activity to the etiology of undifferentiated soft tissue sarcomas for the first time. Implications: The finding that activation of Gli2 transcription factor is sufficient to induce Ewing-like sarcomas provides a direct transformative role of the Hh signaling pathway in undifferentiated soft tissue sarcoma.