Citation

Hettmer S, Liu J, Miller CM, Lindsay MC, Sparks CA, Guertin DA, Bronson RT, Langenau DM, Wagers AJ. 2011. Sarcomas induced in discrete subsets of prospectively isolated skeletal muscle cells. Proceedings of the National Academy of Sciences of the United States of America. 108(50):20002-7. Pubmed: 22135462 DOI:10.1073/pnas.1111733108

Abstract

Soft-tissue sarcomas are heterogeneous cancers that can present with tissue-specific differentiation markers. To examine the cellular basis for this histopathological variation and to identify sarcoma-relevant molecular pathways, we generated a chimeric mouse model in which sarcoma-associated genetic lesions can be introduced into discrete, muscle-resident myogenic and mesenchymal cell lineages. Expression of Kirsten rat sarcoma viral oncogene [Kras(G12V)] and disruption of cyclin-dependent kinase inhibitor 2A (CDKN2A; p16p19) in prospectively isolated satellite cells gave rise to pleomorphic rhabdomyosarcomas (MyoD-, Myogenin- and Desmin-positive), whereas introduction of the same oncogenetic hits in nonmyogenic progenitors induced pleomorphic sarcomas lacking myogenic features. Transcriptional profiling demonstrated that myogenic and nonmyogenic Kras; p16p19(null) sarcomas recapitulate gene-expression signatures of human rhabdomyosarcomas and identified a cluster of genes that is concordantly up-regulated in both mouse and human sarcomas. This cluster includes genes associated with Ras and mechanistic target of rapamycin (mTOR) signaling, a finding consistent with activation of the Ras and mTOR pathways both in Kras; p16p19(null) sarcomas and in 26-50% of human rhabdomyosarcomas surveyed. Moreover, chemical inhibition of Ras or mTOR signaling arrested the growth of mouse Kras; p16p19(null) sarcomas and of human rhabdomyosarcoma cells in vitro and in vivo. Taken together, these data demonstrate the critical importance of lineage commitment within the tumor cell-of-origin in determining sarcoma histotype and introduce an experimental platform for rapid dissection of sarcoma-relevant cellular and molecular events.

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Photo of Amy Wagers

Amy Wagers seeks to change the way we repair our tissues after an injury. Her research focuses on defining the factors and mechanisms that regulate the migration, expansion, and regenerative potential of adult blood-forming and muscle-forming stem cells.

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