An immunocompetent mouse model of liposarcoma

Liposarcoma (LPS) is the most prevalent soft tissue sarcoma. The most common biological subtypes are well-differentiated (WDLPS), a low-grade disease that can evolve to high-grade dedifferentiated LPS (DDLPS), with increased rates of recurrence and metastasis and low response rates to chemotherapy and targeted therapies. Preclinical testing of immunotherapeutics for LPS has been held back by the lack of an immunocompetent mouse model. Here, we present a spontaneous immunocompetent LPS mouse model, ACPP, with targeted deletion of Trp53 and Pten in adipocytes to mimic signaling alterations observed in human LPS. Similar to human LPS, tumors arising in ACPP mice produce WDLPS and DDLPS, along with tumors that exhibit both WD and DD components. Murine and human DDLPS tumors possess transcriptional similarities, including increased expression of oncogenes Cdk4 and Hmga2 and reduced expression of the tumor suppressor Cebpa; further, both mouse and human DDLPS exhibit either high or low T cell infiltration. Syngeneic cell lines derived from spontaneous ACPP DDLPS reliably produce tumors following orthotopic injection, each with distinct growth patterns, aggressiveness and tumor infiltrating lymphocyte profiles. These models provide much needed tools to understand the complex immunobiology of LPS and greatly accelerate the pace of preclinical studies to uncover new therapies for patients with this aggressive malignancy.