MDM2 Derived from Dedifferentiated Liposarcoma Extracellular Vesicles Induces MMP2 Production from Preadipocytes

Abstract

Dedifferentiated liposarcoma (DDLPS) is frequently diagnosed late, and patients typically respond poorly to treatments. DDLPS is molecularly characterized by wild-type p53 and amplification of the MDM2 gene, which results in overexpression of MDM2 protein, a key oncogenic process in DDLPS. In this study, we demonstrate that extracellular vesicles derived from patients with DDLPS or from DDLPS cell lines are carriers of MDM2 DNA that can be transferred to preadipocytes, a major and ubiquitous cellular component of the DDLPS tumor microenvironment, leading to impaired p53 activity in preadipocytes and increased proliferation, migration, and production of matrix metalloproteinase 2; treatment with MDM2 inhibitors repressed these effects. Overall, these findings indicate that MDM2 plays a crucial role in DDLPS by enabling cross-talk between tumor cells and the surrounding microenvironment and that targeting vesicular MDM2 could represent a therapeutic option for treating DDLPS.Significance: Extracellular vesicles derived from dedifferentiated liposarcoma cells induce oncogenic properties in preadipocytes.

Integrated Genomic and Transcriptomic Analysis Revealed Mutation Patterns of De-differentiated Liposarcoma and Leiomyosarcoma

“…Notably high gene copy ampli cation and expression of MDM2 and CDK4 are detected. The two genes have been reported to promote the transformation of mesenchymal cells to DDLPS and it was suggested that they work together in the process (30,(35)(36)(37). A simultaneous detection of highly upregulated gene expression upregulation and gene copy number of both genes in this report further strengths their role in DDLPS tumorigenesis.…”

“…It encodes a nuclear-localized E3 ubiquitin ligase and plays an important role in cell cycle regulation. Its copy number gain has been implicated in cancers including DDLPS (35,36). We also observed the gene copy number of MDM2 is correlated with its mRNA in DDLPS ( Figure 5A).…”

Cracking the riddle of dedifferentiated liposarcoma: is EV-MDM2 a key?

“…Amplification of MDM2 DNA is readily demonstrable by fluorescence in situ hybridization (FISH) and it commonly used to diagnose DDLPS [21]. We have shown that circulating EV-MDM2 DNA copy number can effectively discriminate DDLPS patients versus normal controls by Receiving Operating Characteristic curve analysis [8]. In these studies, the area under the curve (AUC) for MDM2 was 95.8% with a 95% confidence interval, indicating robust separation of DDLPS patients from healthy controls.…”

“…We have discovered that DDLPS extrude extracellular vesicles (EVs), and they are involved in intercellular communication between DDLPS and recipient microenvironment cells such as P-a [8]. This interaction can result in transfer of protein, nucleic acids, and other biologically active molecules, and may contribute to tumor progression [8].…”

“…DDLPS EVs are transferred to recipient microenvironment P-a cells [8]. When exposed to DDLPS EVs, P-a can exhibit some phenotypic characteristics of cancer cells; e.g., enhanced proliferation and migration compared to cells incubated with EV-depleted medium.…”