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Vanished MDM2 amplification in a poorly differentiated sarcoma with amplified TERT-TRIO fusion gene: a targeted effect of radiotherapy?

ABSTRACT: The identification of genetic alterations in sarcoma may give precious clues for the diagnosis. The detection of MDM2 amplification has an important impact since it may orientate towards a dedifferentiated liposarcoma (DDLPS) or more rarely towards an intimal sarcoma. Here we describe a poorly differentiated sarcoma initially diagnosed as a DDLPS, mainly on the basis of FISH analysis that detected MDM2 amplification. The patient was treated by adjuvant radiotherapy and, when the tumor recurred a few years later, MDM2 amplification was not observed anymore. We report the clinical, immunohistological, genomic and molecular description of the primary tumors and his recurrences.

ORGANISM(S): Homo sapiens

PROVIDER: GSE200434 | GEO | 2022/04/08

REPOSITORIES: GEO

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

Project description: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 23 differentially abundant metabolites across both panels (FDR < 0.05, log2 FC < 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.

2020-05-22 | ST001405 | MetabolomicsWorkbench

PAIS experiment

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Neoadjuvant immune checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/trunk undifferentiated pleomorphic sarcoma (NCT03307616)

Project description:Recent evidence suggests that immune checkpoint blockade (ICB) has some activity in metastatic dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS). We conducted a randomized, non-comparative phase 2 trial (NCT03307616) of nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n=17) and extremity/truncal UPS (n=10), with UPS patients receiving concurrent radiation therapy. The primary endpoint of pathologic response as assessed by percent hyalinization was observed to be a median of 8.8% in DDLPS patients and 89% in UPS patients and similar in nivolumab and ipilimumab/nivolumab arms in both cohorts . Higher intratumoral densities of T-regulatory cells were associated with absence of pathologic response (hyalinization<30%). Tumor infiltration by B-cells was associated with higher densities of T-regulatory cells before treatment; this association was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB with concurrent radiation may have significant efficacy in UPS and is associated complex immune changes in the tumor microenvironment in DDLPS and UPS.

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Project description:Invasive subtypes of lung adenocarcinoma (LUAD) show MDM2 amplification that is associated with poor survival. Mouse double minute 2 (MDM2) is frequently amplified in lung adenocarcinoma (LUAD) and is a negative regulator of p53, which binds to p53 and regulates its activity and stability. Genomic amplification and overexpression of MDM2 together with genetic alterations in p53 leads to genomic and genetic heterogeneity in LUAD that represents a therapeutic target. In vitro assays in a panel of LUAD cell lines showed that tumor cell response to MDM2 targeted therapy is associated with MDM2 amplification.

2022-12-31 | GSE191171 | GEO

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2024-01-03 | PXD047297 | iProX

Vanished MDM2 amplification in a poorly differentiated sarcoma with amplified TERT-TRIO fusion gene: a targeted effect of radiotherapy?

Project description:Vanished MDM2 amplification in a poorly differentiated sarcoma with amplified TERT-TRIO fusion gene: a targeted effect of radiotherapy?

| PRJNA824501 | ENA

CDK4 inhibition diminishes p53 activation by Mdm2-antagonists

Project description:CDK4 inhibitors have reached clinical approval for cancer therapy. In parallel, the p53 antagonist Mdm2 remains an attractive target for anti-cancer therapy, including numerous clinical studies. The genes encoding Mdm2 and CDK4 are frequently co-amplified in human malignancies, most notably in liposarcomas, suggesting their combined targeting for therapy. Here we show, however, that small compounds that inhibit Mdm2 and CDK4 antagonize each other rather than synergize in their cytotoxicity towards sarcoma cells. CDK4 inhibition attenuates the induction of p53-responsive genes upon Mdm2 inhibition, and similar results were obtained when depleting Mdm2 and/or CDK4 with siRNA. CDK4 inhibitors also interfered with p53 activity in response to DNA damage. CDK4 inhibition did not reduce p53 binding or histone acetylation to promoters, but rather attenuated the subsequent recruitment of RNA polymerase II. The complexes of p53 and Mdm2, as well as CDK4 and Cyclin D1, physically associated with each other. Upon combined inhibition of Mdm2 and CDK4/6, the interaction of this complex was impaired. Thus, the CDK4-Cyclin D1 complex plays a key role in enabling the transcription of p53 target genes. Taken together, our results raise caution regarding the combination of CDK4 inhibitors with Mdm2 antagonists or conventional DNA-damaging chemotherapeutics in the clinics. Moreover, they suggest a hitherto unknown role for CDK4-cyclin D1 complex in sustaining p53 activity, possibly focusing p53-mediated transcription on actively proliferating cells.

2018-09-20 | GSE113369 | GEO

Analysis of gene expression in p53-null cell types following deletion of Mdm2

Project description:RNA-sequencing was performed to gain insight into the mechanism responsible for the apoptosis and cell cycle arrest induced by loss of Mdm2 in p53-null cells. Following CreERT2-mediated deletion of Mdm2 in three p53-null cell types (T cell lymphoma, sarcoma, and fibroblasts), RNA-sequencing was performed. This high-throughput data revealed Mdm2 deletion in p53-null cells upregulated p53/p73 transcriptional target genes known to induce apoptosis and cell cycle arrest.

2017-09-06 | GSE98705 | GEO

Charting the impact of supraphysiologic MDM2 on gene regulatory circuits in sarcoma

Project description:Amplification of the ubiquitin ligase MDM2 is a common mechanism of P53 inactivation across human tumors. Here we investigated the impact of supraphysiologic MDM2 expression on chromatin topology, gene expression and cellular phenotypes in liposarcoma tumors and models. We identified three independent gene regulatory circuits that predominate in aggressive, dedifferentiated tumors. RUNX and AP-1 family transcription factors bind a shared set of enhancers associated with mesenchymal lineage genes that underlie the developmental state of these tumors. P53 and MDM2 co-occupy enhancers and promoters associated with P53 pathways. When highly expressed, MDM2 also binds an additional set of P53-independent promoters that engage in multi-way physical interactions and regulate genes involved in cell division, RNA splicing, translation and stress responses. We find that liposarcoma cells with low to moderate MDM2 levels are sensitive to P53 inhibitors and their combination with pro-apoptotic agents, but that cells with very high-level MDM2 amplification and expression resist treatment. Hence, heterogeneity of MDM2 expression between and within tumors may compromise therapeutic regimens. In conclusion, we distinguished P53-dependent and P53-independent circuits in MDM2 copy number amplified tumors whose interplay has implications for targeted therapy.

2023-04-10 | GSE213300 | GEO

Identification of the RNAs that bind with MDM2 by high-throughput RIP-seq in MDA-MB-231 and MCF-7 cells

Project description:The E3 ligase MDM2 promotes tumor growth and progression by inducing ubiquitin-mediated degradation of P53 and other tumor suppressing proteins. Here, we identified an MDM2-interacting lncRNA NRON, which promotes tumor formation by suppressing both P53-dependent and independent pathways. NRON binds to MDM2 and MDMX (MDM4) via two different stem-loops respectively and induces their heterogenous dimerization, thereby enhancing the E3 ligase activity of MDM2 towards its tumor suppressing substrates, including P53, RBI and NFATI, etc.

2023-06-19 | GSE226511 | GEO

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