MDM2-Dependent Rewiring of Metabolomic and Lipidomic Profiles in Dedifferentiated Liposarcoma Models

Dedifferentiated liposarcoma (DDLPS) is an aggressive mesenchymal cancer marked by amplification of MDM2, an inhibitor of the tumor suppressor TP53. DDLPS patients with higher MDM2 amplification have lower chemotherapy sensitivity and worse outcome than patients with lower MDM2 amplification. We hyp...

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Published inCancers Vol. 12; no. 8; p. 2157
Main Authors Patt, Andrew, Demoret, Bryce, Stets, Colin, Bill, Kate-Lynn, Smith, Philip, Vijay, Anitha, Patterson, Andrew, Hays, John, Hoang, Mindy, Chen, James L., Mathé, Ewy A.
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 04.08.2020
MDPI
Subjects
Amino acids
Cell culture
Chemoresistance
Chemotherapy
Lipid metabolism
Lipids
Liposarcoma
MDM2 protein
Mesenchyme
Metabolism
Metabolites
Metabolomics
Molecular modelling
p53 Protein
Peptides
Phenotypes
Physiological aspects
Tumor suppressor genes
Tumors
United States
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Summary:Dedifferentiated liposarcoma (DDLPS) is an aggressive mesenchymal cancer marked by amplification of MDM2, an inhibitor of the tumor suppressor TP53. DDLPS patients with higher MDM2 amplification have lower chemotherapy sensitivity and worse outcome than patients with lower MDM2 amplification. We hypothesized that MDM2 amplification levels may be associated with changes in DDLPS metabolism. Six patient-derived DDLPS cell line models were subject to comprehensive metabolomic (Metabolon) and lipidomic (SCIEX 5600 TripleTOF-MS) profiling to assess associations with MDM2 amplification and their responses to metabolic perturbations. Comparing metabolomic profiles between MDM2 higher and lower amplification cells yielded a total of 17 differentially abundant metabolites across both panels (FDR < 0.05, log2 fold change < 0.75), including ceramides, glycosylated ceramides, and sphingomyelins. Disruption of lipid metabolism through statin administration resulted in a chemo-sensitive phenotype in MDM2 lower cell lines only, suggesting that lipid metabolism may be a large contributor to the more aggressive nature of MDM2 higher DDLPS tumors. This study is the first to provide comprehensive metabolomic and lipidomic characterization of DDLPS cell lines and provides evidence for MDM2-dependent differential molecular mechanisms that are critical factors in chemoresistance and could thus affect patient outcome.
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These authors contributed equally to this work.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers12082157