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

Andrew Patt,Andrew Patterson,Bryce Demoret,Colin Stets,Philip Smith,Ewy A Mathé,James L Chen,John Hays,Kate-Lynn Bill,Anitha Vijay,Mindy Hoang

doi:10.3390/cancers12082157

Abstract

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.

Highlights

Dedifferentiated liposarcoma (DDLPS) is a highly morbid, adipocytic tumor accounting for approximately 20% of all soft-tissue sarcomas [1]
That treatment impact on DDLPS tumors differs for tumors with higher vs. lower mouse double minute 2 homolog (MDM2) amplification, we measured the metabolomic and lipidomic effects of MDM2 amplification, MDM2 inhibition, cholesterol inhibition, and ceramide treatment in six patient-derived
Treatment of the cell lines with varying doses of doxorubicin confirmed that MDM2 higher cell lines had lower chemosensitivity than

Summary

Introduction

Dedifferentiated liposarcoma (DDLPS) is a highly morbid, adipocytic tumor accounting for approximately 20% of all soft-tissue sarcomas [1]. Cancers 2020, 12, 2157 spontaneously rather than from preexisting benign lesions, and most patients lack recognized causative factors. Complete surgical resection can be curative, DDLPS often develops in deep anatomic locations, such as the retroperitoneum or mediastinum, where its propensity to encase vital structures typically renders a complete surgical resection difficult or impossible. The five year survival of patients with these abdominal liposarcomas is only 20% [2]. Chemotherapy has limited efficacy in the treatment of DDLPS, with single-agent response rates of up to 30% [3]. Systemic therapeutic regimens improve survival only modestly when complete surgical resection is not feasible [3]. Improved treatments are critically needed for this highly morbid disease

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