A metabolic crosstalk between liposarcoma and muscle sustains tumor growth

• Published in: Nature communications Vol. 15; no. 1; pp. 7940 - 15
• Main Authors: Manteaux, Gabrielle, Amsel, Alix, Riquier-Morcant, Blanche, Prieto Romero, Jaime, Gayte, Laurie, Fourneaux, Benjamin, Larroque, Marion, Gruel, Nadège, Quignot, Chloé, Perot, Gaelle, Jacq, Solenn, Cisse, Madi Y., Pomiès, Pascal, Sengenes, Coralie, Chibon, Frédéric, Heuillet, Maud, Bellvert, Floriant, Watson, Sarah, Carrere, Sebastien, Firmin, Nelly, Riscal, Romain, Linares, Laetitia K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.09.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/21; 38; 38/39; 631/67/1798; 631/67/2327; 631/67/327; 64/60; 82/29; 82/58; 82/80; 96/31; Addictions; Animals; c-Met protein; Cell death; Cell Line, Tumor; Cell Proliferation; Cell survival; Chromatin; Female; Humanities and Social Sciences; Humans; Life Sciences; Liposarcoma; Liposarcoma - genetics; Liposarcoma - metabolism; Liposarcoma - pathology; Male; MDM2 protein; Metabolism; Mice; Monoclonal antibodies; multidisciplinary; Muscle, Skeletal; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; p53 Protein; Proto-Oncogene Proteins c-mdm2; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - metabolism; Science; Science (multidisciplinary); Serine; Serine - metabolism; Tumor Suppressor Protein p53; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Tumors; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-51827-3

Dedifferentiated and Well-differentiated liposarcoma are characterized by a systematic amplification of the Murine Double Minute 2 ( MDM2 ) oncogene. We demonstrate that p53-independent metabolic functions of chromatin-bound MDM2 are exacerbated in liposarcoma and mediate an addiction to serine metabolism to sustain tumor growth. However, the origin of exogenous serine remains unclear. Here, we show that elevated serine levels in mice harboring liposarcoma-patient derived xenograft, released by distant muscle is essential for liposarcoma cell survival. Repressing interleukine-6 expression, or treating liposarcoma cells with Food and Drugs Administration (FDA) approved anti-interleukine-6 monoclonal antibody, decreases de novo serine synthesis in muscle, impairs proliferation, and increases cell death in vitro and in vivo. This work reveals a metabolic crosstalk between muscle and liposarcoma tumor and identifies anti-interleukine-6 as a plausible treatment for liposarcoma patients. During tumorigenesis, liposarcoma has been reported to develop a dependence on serine metabolism but it is unclear how this high energetic demand is met. Here, the authors identify a crosstalk mechanism between tumor and distant muscle cells wherein liposarcoma cell-derived IL-6 drives muscle cell release of serine, in turn accelerating tumor growth.