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Two faces of MDM2: The oncogene MDM2 is best known for encoding a protein that helps degrade p53, a key tumor suppressor. However, it also has other oncogenic effects, and Cissé et al. have uncovered one that affects serine metabolism in liposarcoma, a type of soft tissue cancer. The authors showed that in this tumor type, MDM2 is recruited to chromatin independent of any interaction of p53. Inhibiting MDM2 impairs serine synthesis and increases the cells' reliance on exogenous serine, which is often in short supply in tumors. The authors then demonstrated that a small-molecule inhibitor of MDM2 impairs liposarcoma growth both in vitro and in patient-derived xenograft models. Well-differentiated and dedifferentiated liposarcomas (LPSs) are characterized by a systematic amplification of the MDM2 oncogene, which encodes a key negative regulator of the p53 pathway. The molecular mechanisms underlying MDM2 overexpression while sparing wild-type p53 in LPS remain poorly understood. Here, we show that the p53-independent metabolic functions of chromatin-bound MDM2 are exacerbated in LPS and mediate an addiction to serine metabolism that sustains nucleotide synthesis and tumor growth. Treatment of LPS cells with Nutlin-3A, a pharmacological inhibitor of the MDM2-p53 interaction, stabilized p53 but unexpectedly enhanced MDM2-mediated control of serine metabolism by increasing its recruitment to chromatin, likely explaining the poor clinical efficacy of this class of MDM2 inhibitors. In contrast, genetic or pharmacological inhibition of chromatin-bound MDM2 by SP141, a distinct MDM2 inhibitor triggering its degradation, or interfering with de novo serine synthesis, impaired LPS growth both in vitro and in clinically relevant patient-derived xenograft models. Our data indicate that targeting MDM2 functions in serine metabolism represents a potential therapeutic strategy for LPS. [ABSTRACT FROM AUTHOR]