Immunocompetent murine models recapitulate the heterogeneous tumor immune microenvironment of human liposarcoma.

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

Experimental design: We developed an autochthonous, immunocompetent LPS mouse model (ACPP) by using targeted Cre-mediated deletion of Trp53 and Pten in adipocytes to mimic the signaling alterations observed in human LPS. 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.

Results: ACPP mice develop WDLPS, 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.

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