Sarcomas are cancers of connective tissue, such as bone, nerves, and muscle. Liposarcoma, a neoplasm arising within adipose tissue, is the most common soft tissue sarcoma. Although most commonly found in the retroperitoneum or thighs, liposarcomas can arise throughout the body and are often large when found. Current treatment is limited to surgery and radiation, with chemotherapy doing little to improve prognosis in advanced cases. Due to the large size of tumors and their proximity to organs and healthy tissue, complete surgical removal is difficult and recurrence rates remain high. Liposarcoma can be divided into three histological subtypes: pleomorphic, myxoid/round cell, and well-/dedifferentiated. Here we demonstrate the generation of three novel dedifferentiated liposarcoma xenograft models from freshly resected patient tissue. These xenograft models and their derived cultured cells successfully recapitulate the morphological and gene expression profiles of their patient tumors throughout serial passage in mice. Interestingly, the patients whose tumors could engraft and be serially passaged had significantly shorter survival than patients whose tumors did not engraft. These tumors carried gene expression signatures with more aggressive and less differentiated features. We then show the use of these newly developed xenografts in pre-clinical studies of

the mTOR inhibitor rapamycin and the multi-kinase inhibitor sorafenib as potential therapies for dedifferentiated liposarcoma. Although only one of the three xenografts responded to treatment with slowed tumor growth, all three tumors show distinct morphological changes in response to combination treatment with rapamycin and sorafenib, such as increased necrosis and decreased cell density. Interestingly, combination treatment also elicited a partial differentiation response as demonstrated by changes in lipid content and gene expression signatures. Taken together, these studies have created a flexible xenograft model that successfully recapitulates the human disease and will serve as a useful tool to further understand this complex disease and screen potential therapies.