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The G-Quadruplex experimental drug QN-302 effectively impairs liposarcoma cell viability by inhibiting MDM2 expression and restoring p53 levels [RNA-seq]

ABSTRACT: Well-differentiated (WD) and dedifferentiated (DD) liposarcomas (LPS) account for ~60% of all liposarcomas, characterized by 12q13–q15 region amplification and aberrant MDM2 expression. Current therapies are limited, particularly for advanced stages, leading to poor outcomes. G-quadruplexes (G4s), secondary structures in G-rich nucleic acid sequences, were identified in the MDM2 P2 promoter. We investigated MDM2 inhibition via small molecule G4 ligands. Laboratory and patient-derived LPS cell lines, and normal pre-adipocytes were analyzed using CUT&Tag, RNA-seq, cell viability, qRT-PCR, Western blot, siRNA, and nascent transcript assays. QN-302, a naphthalene diimide (NDI)-derivative, emerged as the most effective G4 ligand, significantly impairing WD/DDLPS cell growth in a dose-dependent manner by stabilizing MDM2 G4 at the P2 promoter, inhibiting polymerase progression, and reducing full-length MDM2 transcripts, leading to p53 accumulation and apoptotic cell death. In vivo, QN-302 reduced tumor volume and was well-tolerated in xenograft models. This novel therapeutic strategy to inhibit MDM2 and reactivate p53 in WD/DDLPS could extend to all tumors with wild-type TP53 and enhance anticancer efficacy when combined with other drugs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271823 | GEO | 2025/01/31

REPOSITORIES: GEO

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The G-Quadruplex experimental drug QN-302 effectively impairs liposarcoma cell viability by inhibiting MDM2 expression and restoring p53 levels [CUT&Tag]

Project description:Well-differentiated (WD) and dedifferentiated (DD) liposarcomas (LPS) account for ~60% of all liposarcomas, characterized by 12q13–q15 region amplification and aberrant MDM2 expression. Current therapies are limited, particularly for advanced stages, leading to poor outcomes. G-quadruplexes (G4s), secondary structures in G-rich nucleic acid sequences, were identified in the MDM2 P2 promoter. We investigated MDM2 inhibition via small molecule G4 ligands. Laboratory and patient-derived LPS cell lines, and normal pre-adipocytes were analyzed using CUT&Tag, RNA-seq, cell viability, qRT-PCR, Western blot, siRNA, and nascent transcript assays. QN-302, a naphthalene diimide (NDI)-derivative, emerged as the most effective G4 ligand, significantly impairing WD/DDLPS cell growth in a dose-dependent manner by stabilizing MDM2 G4 at the P2 promoter, inhibiting polymerase progression, and reducing full-length MDM2 transcripts, leading to p53 accumulation and apoptotic cell death. In vivo, QN-302 reduced tumor volume and was well-tolerated in xenograft models. This novel therapeutic strategy to inhibit MDM2 and reactivate p53 in WD/DDLPS could extend to all tumors with wild-type TP53 and enhance anticancer efficacy when combined with other drugs.

2025-01-31 | GSE271822 | GEO

The Potent G-Quadruplex-Binding Compound QN-302 Downregulates S100P Gene Expression in Cells and in an In Vivo Model of Pancreatic Cancer

Project description:The naphthalene diimide compound QN-302, designed to bind to G-quadruplex DNA sequences within the promoter regions of cancer-related genes, has high anti-proliferative activity in pancreatic cancer cell lines and anti-tumor activity in several experimental models for the disease. We show here that QN-302 also causes down-regulation of the expression of the S100P gene and the S100P protein in cells and in vivo. This protein is well-established as being involved in key proliferation and motility pathways in several human cancers and has been identified as a potential biomarker in pancreatic cancer. The S100P gene contains 60 putative quadruplex-forming sequences, one of which is in the promoter region, 48 nucleotides up-stream from the transcription start site. We report biophysical and molecular modeling studies showing that this sequence forms a highly stable G-quadruplex in vitro, which is further stabilized by QN-302. We also report transcriptome analyses showing that S100P expression is highly upregulated in tissues from human pancreatic cancer tumors, compared to normal pancreas material. The extent of up-regulation is dependent on the degree of differentiation of tumor cells, with the most poorly differentiated, from more advanced disease, having the highest level of S100P expression. The experimental drug QN-302 is currently in pre-IND development (as of Q1 2023) and its ability to down-regulate S100P protein expression supports a role for this protein as a marker of therapeutic response in pancreatic cancer. These results are also consistent with the hypothesis that the S100P promoter G-quadruplex is a potential therapeutic target in pancreatic cancer at the transcriptional level for QN-302.

2023-04-01 | GSE226307 | GEO

Epigenetic profiling of well differentiated and dedifferentiated liposarcoma identifies H3K9me3 and Kruppel-like factor 6 (KLF6) as determinants of aggressiveness in sarcoma (expression)

Project description:Little is known about the epigenomics of liposarcoma (LPS). Here, we profiled the global expression of 9 epigenetic marks in well differentiated (WD) and dedifferentiated (DD) LPS from 151 patients and found increased H3K9me3 among DDLPS tumors. We performed ChIP-seq and gene expression profiling of patient derived cell lines to discover functionally significant regions of differential H3K9me3 enrichment between WDLPS and DDLPS associated with concomitant gene expression changes. We performed genome-wide transcriptional profiling of dedifferentiated liposarcoma (DDLPS) and well differentiated liposarcoma (WDLPS) cell lines using the Affymetrix U133A GeneChip array

2015-08-04 | E-GEOD-57750 | biostudies-arrayexpress

Epigenetic profiling of well differentiated and dedifferentiated liposarcoma identifies H3K9me3 and Kruppel-like factor 6 (KLF6) as determinants of aggressiveness in sarcoma (ChIP-seq)

Project description:Little is known about the epigenomics of liposarcoma (LPS). Here, we profiled the global expression of 9 epigenetic marks in well differentiated (WD) and dedifferentiated (DD) LPS from 151 patients and found increased H3K9me3 among DDLPS tumors. We performed ChIP-seq and gene expression profiling of patient derived cell lines to discover functionally significant regions of differential H3K9me3 enrichment between WDLPS and DDLPS associated with concomitant gene expression changes. We performed genome-wide transcriptional profiling of H3K9me3 in dedifferentiated liposarcoma DDLPS and well differentiated liposarcoma WDLPS cell lines.

2015-08-04 | E-GEOD-57749 | biostudies-arrayexpress

Epigenetic profiling of well differentiated and dedifferentiated liposarcoma identifies H3K9me3 and Kruppel-like factor 6 (KLF6) as determinants of aggressiveness in sarcoma (expression)

2015-08-04 | GSE57750 | GEO

Epigenetic profiling of well differentiated and dedifferentiated liposarcoma identifies H3K9me3 and Kruppel-like factor 6 (KLF6) as determinants of aggressiveness in sarcoma (ChIP-seq)

2015-08-04 | GSE57749 | GEO

Cellular origin and clonal evolution of human dedifferentiated liposarcoma

Project description:Dedifferentiated liposarcoma (DDLPS) is the most frequent high-grade soft tissue sarcoma subtype. It is characterized by a component of undifferentiated tumor cells coexisting with a component of well-differentiated adipocytic tumor cells. Both dedifferentiated (DD) and well-differentiated (WD) components exhibit MDM2 amplification, however their cellular origin remains elusive. Using single-cell RNA sequencing and functional assays in paired WD and DD components from primary DDLPS tumors, we characterized the cellular heterogeneity of DDLPS tumor and micro-environment. We identified a population of tumor adipocyte stem cells (ASC) showing striking similarities with adipocyte stromal progenitors found in white adipose tissue. We show that tumor ASC harbor the ancestral genomic alterations of WD and DD components, suggesting that both derive from these progenitors following clonal evolution. Last, we show that DD tumor cells keep important biological properties of ASC including pluripotency and that their adipogenic properties are inhibited by a TGF-β high immunosuppressive tumor micro-environment.

2024-07-22 | GSE221493 | GEO

Cellular origin and clonal evolution of human dedifferentiated liposarcoma

2024-07-22 | GSE221492 | GEO

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

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

Project description: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.

2022-04-08 | GSE200434 | GEO

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