American Association for Cancer Research
15417786mcr180117-sup-196585_4_supp_5252287_pkpvxl.pdf (5.62 MB)

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

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journal contribution
posted on 2023-04-03, 16:48 authored by Jonathan T. Fleming, Emily Brignola, Lei Chen, Yan Guo, Shilin Zhao, Quan Wang, Bingshan Li, Hernán Correa, Alexandre N. Ermilov, Andrzej A. Dlugosz, Chin Chiang

Figure S1. PCG2 tumors showed persistent Hh pathway activity, while SmoM2 disrupts brain morphogenesis. Figure S2. PCG2 gene expression and ultrastructural features. Figure S3. Characterization of PCG2M226 cells. Figure S4. Phenotypic divergence between PCG2; Gli1nlacZ and PCG2 tumors. Figure S5. Fate-mapping of Pcp2-cre lineage cells.



University of Michigan Rogel Cancer Center

Vanderbilt-Ingram Cancer Center



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 PCG2, 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 PCG2 mice featured some characteristics that were reminiscent of Ewing sarcoma. Even though it is widely understood that Ewing sarcoma 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 Ewing sarcoma, 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 naïve mesenchymal progenitors originate tumors in PCG2 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.

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