Use of cellular context to determine sarcoma phenotype in a new mouse sarcoma model.

Abstract 10029 Background: Soft-tissue sarcomas are heterogeneous malignancies of mesodermal, non-hematopoietic origin. They may present with tissue-specific differentiation, such as myogenic features in rhabdomyosarcoma. However, the cellular origins of sarcomas in skeletal muscle have remained controversial. This study sought to investigate the effects of cell context on the outcome of sarcoma-associated genetic lesions by ex-vivo genetic perturbation and orthotopic implantation of muscle satellite cells (sorted as CD45(-)MAC1(-)TER119(-)Sca1(-)β1-integrin(+)CXCR4(+) cells) and non-myogenic precursors (sorted as CD45(-)MAC1(-)TER119(-)Sca1(+) cells), freshly isolated by fluorescence-activated cell sorting from p16p19(null)mouse skeletal muscle, infected with Kras(G12V)-pGIPZ-IRES-GFP lentivirus, and injected into the gastrocnemius muscles of immunocompromised NOD.SCID mice. We show that mouse Kras-expressing; p16p19(null) muscle satellite cells can serve as cells-of-origin for mouse rhabdomyosarcomas (MyoD, Myogenin and Desmin positive) with non-alveolar, pleomorphic features. Conversely, Kras-expressing; p16p19(null) non-myogenic progenitors typically induce non-myogenic, pleomorphic sarcomas (MyoD, Myogenin and Desmin negative). Despite initiation in distinct cells-of-origin, Kras; p16p19(null) sarcomas share a common, Ras-predominated transcriptional signature that is enriched in human soft-tissue sarcomas and suggests that Ras-pathway activation is an important event in human sarcomas. Moreover, our bioinformatic analyses identify a small group of genes that are upregulated in sarcomas across species and may hold broad therapeutic relevance. In summary, we have established a highly tractable chimeric mouse model for the induction of sarcomas in skeletal muscle, which demonstrates that the lineage commitment of the target cell into which oncogenetic hits are introduced is critical in determining sarcoma phenotype. This new sarcoma model recapitulates genetic events in human soft-tissue sarcomas, can be used as a platform to dissect the cellular and genetic events responsible for sarcoma development and may accelerate future therapeutic discovery efforts in the sarcoma field.