Abstract 1361: Sarcoma-relevant genetic events identified in a chimeric mouse model of sarcoma in skeletal muscle

Abstract

Abstract Background. Soft-tissue sarcomas are heterogeneous malignancies of mesodermal, non-hematopoietic origin. Ex-vivo genetic alteration (by activation of Kras(G12V) and deletion of p16INK4A/p19ARF) and intramuscular implantation of discrete mesodermal cell populations, freshly isolated from mouse skeletal muscle, results in the rapid induction of pleomorphic sarcomas. This model system can be utilized as a platform to dissect sarcoma-relevant cellular and genetic events. Methods. The molecular underpinnings of Kras; p16p19null sarcomas were evaluated by whole genome microarray in comparison to normal muscle and to previously published human rhabdomyosarcoma datasets. Upregulation of 141 candidate genes identified by bioinformatic analyses was verified using a customized RT*2 Profiler™ PCR Array (SA Biosciences). The effects of shRNA knockdown of candidate genes on sarcoma growth were evaluated in sarcoma cell lines. Results. Kras; p1619null sarcomas recapitulate gene expression signatures of human rhabdomyosarcomas and identify a conserved cluster of 144 genes that is concordantly upregulated in both mouse and human sarcomas compared to normal skeletal muscle. 74 of these 144 genes have been associated previously with human malignancies, and 28 have been linked specifically to sarcomas. PCR array validation confirmed that 104 of these genes are upregulated in mouse sarcomas compared to normal skeletal muscle, including the BMP antagonist and Shh morphogen Gremlin, previously implicated in human sarcomas (upregulated 1327-fold in mouse sarcomas vs. muscle). Gremlin knockdown in sarcoma cell lines by shRNA results in reduced proliferation, thereby implicating a functional role in sarcoma biology. Conclusions. Our studies identify a small group of genes that are upregulated in sarcomas across species and may be of fundamental importance in sarcomas. Future studies of the genes identified here will likely provide important insights into the events that drive sarcomas in muscle, and identify new targets for therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1361. doi:1538-7445.AM2012-1361