Skeletal Muscle Stem Cells and Progenitors as Cells of Origin in Sarcoma

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Date

2013

Authors

Blum, Jordan M

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Kirsch, David G

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Abstract

Soft tissue sarcomas are rare malignancies that derive from connective tissue. Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, while undifferentiated pleomorphic sarcoma (UPS) is one of the most common soft tissue sarcomas diagnosed in adults. To investigate the cell(s) of origin of these sarcomas in the myogenic lineage, I used the tamoxifen-inducible CreERT2-loxP system in vitro and in vivo. Pax7-CreERT2 and MyoD-CreERT2 mice were utilized to transform Pax7+ and MyoD+ myogenic progenitors by expressing oncogenic K-rasG12D and deleting p53 in vivo. After injection of systemic tamoxifen into Pax7-CreERT2 and MyoD-CreERT2 mice, primary myogenic sarcomas including mouse rhabdomyosarcoma (mRMS) and mouse UPS (mUPS) developed within 2 to 6 months at various anatomical sites. Using unsupervised gene expression analysis, mRMS from Pax7+ myogenic progenitors clustered separately from the mUPS generated from the Pax7+ myogenic progenitors, as well as the mUPS generated by MyoD+ myogenic progenitors. These results suggest that Pax7+ and MyoD+ myogenic progenitor cells are tumor-initiating cells mUPS and that Pax7+MyoD- progenitors are tumor initiating cells for mRMS. These results demonstrate that mRMS and mUPS lie along a continuum. Furthermore, by comparing these tumors to their cell of origin, we find that Hedgehog signaling is dysregulated by increased expression of activated Gli3 in the sarcomas. Knockdown of Gli3 in cell lines derived from mouse and human sarcomas blocks tumor cell proliferation. I have established two novel mouse models of sarcoma with rapid onset and high penetrance, which may be useful for identifying novel therapies in sarcoma.

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Blum, Jordan M (2013). Skeletal Muscle Stem Cells and Progenitors as Cells of Origin in Sarcoma. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/7171.

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