Immunocompetent Murine Models Recapitulate the Heterogeneous Tumor-Immune Microenvironment of Human Liposarcoma

Liposarcoma is the most common soft tissue sarcoma. Well-differentiated liposarcoma can progress to dedifferentiated liposarcoma (DDLPS), a more aggressive form with higher metastatic potential and poor response to existing therapies. Progress in understanding and treating liposarcoma has been limited. To address this, we sought to develop an immunocompetent genetically engineered mouse model of liposarcoma.

We developed an autochthonous, immunocompetent liposarcoma mouse model [AAV8-Ap2.2-eGFP/Cre Ptenf/f;Trp53f/f C57BL/6 (ACPP)] by using targeted Cre-mediated deletion of Trp53 and Pten in adipocytes to mimic the signaling alterations observed in human liposarcoma. We characterized the histology, transcriptional features, and tumor microenvironment of this model. Additionally, we established syngeneic cell lines derived from ACPP DDLPS tumors and evaluated them for tumor formation, growth dynamics, and immune composition after implantation.

ACPP mice develop well-differentiated liposarcoma, DDLPS, and mixed tumors, mirroring human disease. Both murine and human DDLPS tumors share key transcriptional features and exhibit heterogeneous T-cell infiltration. Syngeneic DDLPS cell lines reliably form tumors in vivo, with each line demonstrating distinct growth kinetics, aggressiveness, and immune profiles.

The ACPP model provides a novel and clinically relevant platform to study liposarcoma in an immunocompetent setting. Along with the ACPP-derived cell lines, these models not only provide essential tools to understand the complex immunobiology of liposarcoma but also can be used to elucidate the underlying molecular mechanisms driving liposarcoma generation and progression and significantly accelerate the pace of preclinical studies aimed at uncovering more effective new therapies for patients with this aggressive malignancy.