Proteogenomic characterization of myxoid liposarcoma reveals molecular features associated with poor prognosis

We performed the first comprehensive proteogenomic analysis of myxoid liposarcoma using 72 surgically resected tumors. Integrated protein-expression profiling and transcriptome-based immune deconvolution identified macrophage migration inhibitory factor (MIF) as a potential factor associated with tumor-associated macrophage differentiation, and immunohistochemistry confirmed that high MIF expression is significantly associated with poor prognosis. Multi-omics clustering revealed that unfavorable myxoid liposarcoma is characterized by heightened phosphorylation of AKT substrates and global up-regulation of transcriptional and translational programs. In particular, BAD hyper-phosphorylation indicated suppression of apoptosis as a previously unrecognized mechanism of disease aggressiveness. We then tested a clinically available drug that re-activates the apoptotic pathway in a myxoid liposarcoma cell line and observed potent antitumor effects at concentrations achievable in the clinic. These findings nominate MIF as a prognostic biomarker and implicate dysregulated apoptotic signaling as a tractable therapeutic vulnerability in high-risk myxoid liposarcoma, offering new biological insight and a potential targeted treatment strategy for patients with poor-prognosis disease. Implications: Proteogenomic profiling reveals that poor-prognosis myxoid liposarcoma is characterized by MIF-associated macrophage remodeling and suppression of apoptosis through AKT–BAD signaling, identifying apoptotic vulnerability as a potential therapeutic opportunity in high-risk disease.