title: Sarcomas induced in discrete subsets of prospectively isolated skeletal muscle cells.
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.
authors.affiliation: The Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Hettmer
authors.forename: Jianing
authors.initials: J
authors.lastname: Liu
authors.forename: Christine M
authors.initials: CM
authors.lastname: Miller
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Lindsay
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Sparks
authors.forename: David A
authors.initials: DA
authors.lastname: Guertin
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: David M
authors.initials: DM
authors.lastname: Langenau
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D019070:Cell Lineage; D049109:Cell Proliferation; D002469:Cell Separation / Q000379:methods*; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D032342:Muscle Cells / Q000473:pathology*; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D019042:Muscle Neoplasms / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D012509:Sarcoma / Q000235:genetics / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059467:Transcriptome; D018631:ras Proteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins