Targeting the metastasis initiating cell in undifferentiated pleomorphic sarcoma

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Undifferentiated pleomorphic sarcoma (UPS) is a soft tissue sarcoma, with one of the worst prognosis. We will build on our discovery that UPS contains a small subpopulation of metastasis initiating cells (MCs) that are enhanced for their ability to form metastasis. Our proof of principle data showed that targeting genes differentially expressed in the MC population inhibits metastasis in UPS tumors established as xenografts in mice. In our preliminary data, we show that epigenetic changes distinguish the MC from the rest of the UPS cell populations. Furthermore, we found that individual cell populations in UPS produce secreted factors that influence behavior of other cell UPS cell populations, acting in a competitive manner. Our hypothesis is that the MC population is maintained by epigenetic changes that endow this subpopulation of cells with distinct properties that drive sarcoma metastasis. We will test this hypothesis by answering the following two questions: 1) What drives the MC population? Here we will build on our preliminary data suggesting that epigenetic events driven by the regulation of histone acetylation and methylation maintain the MC. The function of differentially expressed genes in the MC in regulating metastatic ability will be assessed using a lung organ on a chip assay and findings will be tested in-vivo in murine tumors. 2) Can pharmacologically targeting the MIC population be used to treat UPS? Here we will build on our gene expression data, CRISPER screens, and results from a high throughput drug screen to identify agents that target the MC. Pharmacologic agents and genetic approaches in murine tumors and human primary UPS tumors established as xenografts in immunodeficient mice to determine their effect on disease progression and metastasis. This proposed work utilizes unique mouse models of sarcoma and human tumors to test novel biologic processes related to cellular heterogeneity in sarcoma. As such, it will provide important biologic insights not only about UPS, but also about cell heterogeneity in cancer in general. In addition, it will lead to the development of new treatment approaches for UPS, a tumor with a poor outcome using currently available therapies.