Abstract 1362: Developing genetically flexible mouse models of sarcoma - a novel functional genomics platform

Abstract Introduction: Sarcomas are a heterogeneous group of malignant neoplasms that arise from connective tissues and have a disease-specific mortality of 30-50%. Existing mouse models of sarcomagenesis utilize knockout and transgenic mice but it is unclear if fixed germline mutations recapitulate sporadic human cancer. In addition, creating germline mutant mice requires substantial time and resources. We hypothesized that delivery of oncogenes into mouse skeletal muscle using a retroviral (RCAS) system would result in sarcomagenesis and could mitigate the limitations of conventional mouse models. Methods: p16/p19 null mice expressing the retroviral receptor, TVA, under nestin (N-tva) or β-actin (BKE) promoters were used. DF1 chicken fibroblasts, infected with avian-leukosis virus vectors (RCAS) carrying combinations of oncogenes (KrasG12D, c-Myc, IGF2) or GFP alone, were delivered by injection into the hindlegs of neonatal mice and tumor development was monitored. Results: GFP-positive cells were observed following in vitro infection of cultured mouse skeletal muscle with RCAS-GFP and GFP+ myoblasts were identified from mice injected with RCAS-GFP in vivo, suggesting successful cell infection and targeted gene delivery. Sarcomas formed in 30% of p16/p19−/−xN-tva mice at the injection site with a median latency of 23.5 weeks (8-42 weeks). Several subtypes of sarcoma developed in this strain based on morphologic assessment and immunohistochemistry (S100, desmin, and smooth muscle actin). Of these, malignant peripheral nerve sheath tumor (MPNST) that overexpressed EGFR consistent with human MPNST, was the predominant subtype (55%). Although a similar tumor incidence occurred in the p16/p19−/−xBKE strain (32%), the median latency was much shorter, 10.4 weeks (7-25 weeks) and the tumor spectrum shifted to predominantly fibrosarcoma (36%) or rhabdomyosarcoma (36%). No tumors were observed in mice injected with empty RCAS vector or without inactivation of the p16/p19 locus. Gene-anchored PCR revealed retroviral vector DNA integration in 89% of N-tva and 97% of BKE tumors. KrasG12D was the most frequent oncogene isolated. Conclusions: We have generated novel models of sarcomagenesis using the RCAS-TVA system to deliver known sarcoma oncogenes into mouse hind legs with a tumor incidence of ∼30%. With optimization, we will be able to use this genetically flexible system to functionally validate novel candidate sarcoma genes. 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 1362. doi:1538-7445.AM2012-1362

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