Characterization of a Mouse Model of Soft Tissue Sarcoma: Intraoperative Molecular Imaging and miRNA Regulation of Metastasis

Abstract

<p>Soft Tissue Sarcomas are a rare group of mesenchymal tumors with over 50 recognized subtypes. These tumors are a diverse group of malignancies that primarily arise from the connective tissue, fat and muscle. In the United States, there are estimated to be approximately 11,000 new diagnoses a year with an annual mortality rate approaching 40%. Unfortunately, with such a diversity of subtypes of soft tissue sarcoma, and the relative scarcity of patient samples, there is a need for animal models that faithfully recapitulate the biology of these tumors. Such animal models would be useful for dissecting the underlying biology of soft tissue sarcomas and to evaluate novel therapies. One such model is the LSL-KrasG12D; p53Flox/Flox mouse model of soft tissue sarcoma. These tumors are generated in a spatial and temporally restricted fashion and closely mimic the natural history of human soft tissue sarcomas, including a predilection to develop lung metastases. Here I will characterize this model of soft tissue sarcoma by: 1) performing cross species genomic comparisons to show that the LSL-KrasG12D; p53Flox/Flox mouse model of soft tissue sarcoma most closely resembles Undifferentiated Pleomorphic Sarcoma , 2) utilizing this mouse model to identify cathepsin proteases as molecular markers of soft tissue sarcoma. I will then use cathepsin activated imaging probes for intraoperative molecular imaging to identify microscopic residual cancer in real time. Finally, 3) I identify a novel mechanism through which MAPK signaling regulates miRNA biogenesis and the development of distant metastases in the LSL-KrasG12D; p53Flox/Flox mouse model of soft tissue sarcoma.</p>