Targeting De Novo Cholesterol Synthesis as a Therapeutic Strategy in Rhabdomyosarcoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE279213 | GEO | 2025/10/10
REPOSITORIES: GEO
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Project description:Alterations of metabolic pathways that sustain cancer cell survival often offer promising therapeutic avenues. Here, we show that enhanced de novo cholesterol biosynthesis is crucial for the survival of head and neck squamous cell carcinoma (HNSCC). Transcriptomic analysis of HNSCC tissues identified profound dysregulation in steroid and cholesterol metabolism compared to normal tissues. Inhibition of two key enzymes, DHCR7 and DHCR24, which mediate cholesterol biosynthesis, induced apoptosis in HNSCC cells, even when cholesterol levels were restored. Metabolomic profiling revealed the accumulation of 7-dehydrocholesterol (7-DHC) upon DHCR7 or DHCR24 inhibition, triggering endoplasmic reticulum (ER) stress and promoting further cell death. These findings suggest that HNSCC cells adapt to ER stress by modulating 7-DHC levels through enhancing DHCR7 and DHCR24 levels, highlighting a metabolic vulnerability in HNSCC and demonstrating a direct link between cholesterol metabolism and ER stress in cancer cell viability.
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Project description:Rhabdomyosarcoma (RMS) presents a significant challenge in the field of oncology as a high-grade, aggressive soft tissue sarcoma that originates from skeletal (striated) muscle cells which do not fully differentiate. This condition is characterized by two major molecular and histopathological subtypes: 'alveolar' RMS (ARMS) and 'embryonic' RMS (ERMS), each driven by unique underlying mechanisms. The disease's inherent heterogeneity, complex genetic makeup, and limited therapeutic options highlight the need for innovative research approaches to understand its complexities. Through the use of transcriptomics, alongside an exploration of proteomics, researchers have identified dysregulated proteins common to both subtypes, offering insights into the pathophysiology and aggressiveness of RMS. Additionally, metabolomics sheds light on metabolic pathways linked to RMS perturbation. The integration of high-throughput omics ‘Multi-omics’ technologies thus provides unprecedented opportunities to dissect the molecular intricacies of cancer biology, offering avenues for enhanced understanding and targeted interventions in RMS.
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Project description:Frozen skeletal muscle, tumor adjacent skeletal muscle, Endothelial Rhabdomyosarcoma (ERMS) and Alveolar Rhabdomyosarcoma (ARMS) samples were profiled on Illumina bead array. Total RNA from primary resected samples were profiled to allow comparison of 1) normal skeletal muscle tissue with RMS samples and 2) ARMS with ERMS tumors.
2013-12-31 | E-GEOD-28511 | biostudies-arrayexpress
Project description:Purpose: This study aims to identify novel targets in the rare pediatric cancer, fusion-positive rhabdomyosarcoma (FP-RMS), and examine differences/similarities in FP-RMS tumor responses to BMI1 (B lymphoma Mo-MLV insert region 1 homolog) inhibition. Methods: FP-RMS cell lines Rh28 and Rh30 were treated with DMSO (vehicle) or PTC-028, a BMI1 inhibitor, and RNA was collected after 24 or 48 hr in triplicate. RNA-seq was performed, and gene expression data were analyzed through Gene Ontology (GO) and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analyses. Data from OncoPPi and the STRING database were also utilized in this study. Results: Both Rh28 and Rh30 had some overlapping pathways affected by PTC-028, notably downregulation of cell cycle progression, the DNA damage response, and cholesterol biosynthesis. Rh30+PTC-028 had more genes containing TEAD-motifs downregulated compared to Rh28+PTC-028. Rh28 and Rh30 also had differing changes in expression in kinases of LATS1/2, EPHA2, and PDGFRA. Conclusion: Overall, these results bring new insights into pathways influenced by BMI1 expression and contrasting intertumor drug responses in FP-RMS.
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Project description:Rhabdomyosarcoma (RMS) is a highly malignant pediatric cancer of skeletal muscle lineage. The aggressive alveolar subtype is commonly characterized by t(2;13) or t(1;13) translocations with the expression of PAX3- or PAX7-FOXO1 fusion transcription factors respectively and is known as fusion positive RMS (FP-RMS). FP-RMS tumors rely on the fusion gene to maintain their proliferative state while avoiding terminal differentiation program. Since disruptions of normal development are likely governed by epigenetic changes in these low-mutational-burden tumors, we investigated the contributions of chromatin regulatory complexes to RMS tumor maintenance. We demonstrate the essentiality of the mSWI/SNF ATPase BRG1 for FP-RMS proliferation and discover that RMS significantly overexpress SMARCA4 (encoding BRG1) compared to skeletal muscle. We define the mSWI/SNF subunit repertoire in FP-RMS and provide evidence for the assembly of multiple mSWI/SNF complexes including canonical BAF, PBAF and non-canonical (nc)BAF in FP-RMS. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which was further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with FP-RMS core regulatory transcription factors. We report that mSWI/SNF complexes act as sensors of chromatin state, which are recruited to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes. Finally, BRG1 targeting compounds reproduce the effects of genetic ablation. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for treating this lethal childhood tumor.
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Project description:Rhabdomyosarcoma (RMS) is a highly malignant pediatric cancer of skeletal muscle lineage. The aggressive alveolar subtype is commonly characterized by t(2;13) or t(1;13) translocations with the expression of PAX3- or PAX7-FOXO1 fusion transcription factors respectively and is known as fusion positive RMS (FP-RMS). FP-RMS tumors rely on the fusion gene to maintain their proliferative state while avoiding terminal differentiation program. Since disruptions of normal development are likely governed by epigenetic changes in these low-mutational-burden tumors, we investigated the contributions of chromatin regulatory complexes to RMS tumor maintenance. We demonstrate the essentiality of the mSWI/SNF ATPase BRG1 for FP-RMS proliferation and discover that RMS significantly overexpress SMARCA4 (encoding BRG1) compared to skeletal muscle. We define the mSWI/SNF subunit repertoire in FP-RMS and provide evidence for the assembly of multiple mSWI/SNF complexes including canonical BAF, PBAF and non-canonical (nc)BAF in FP-RMS. Proteomic studies suggest proximity between PAX3-FOXO1 and BAF complexes, which was further supported by genome-wide binding profiles revealing enhancer colocalization of BAF with FP-RMS core regulatory transcription factors. We report that mSWI/SNF complexes act as sensors of chromatin state, which are recruited to sites of de novo histone acetylation. Phenotypically, interference with mSWI/SNF complex function induces transcriptional activation of the skeletal muscle differentiation program associated with MYCN enhancer invasion at myogenic target genes. Finally, BRG1 targeting compounds reproduce the effects of genetic ablation. We conclude that inhibition of BRG1 overcomes the differentiation blockade of FP-RMS cells and may provide a therapeutic strategy for treating this lethal childhood tumor.
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Project description:Rhabdomyosarcoma (RMS) is a frequent non-epithelial tumor of soft tissue that originates from a myogenic differentiation defect. Expression of SNAIL transcription factor is elevated in the alveolar subtype of RMS, characterized by a low myogenic differentiation status and high aggressiveness. SNAIL affects RMS metastasis by reorganization of actin cytoskeleton, regulation of ezrin expression and chemotaxis to HGF and SDF-1. The differentiation of human RMS diminishes SNAIL level. SNAIL silencing completely abolishes the growth of human RMS xenotransplants. SNAIL inhibits myogenic differentiation of RMS by binding to the MYF5 promoter, suppressing its expression, displacing MYOD from canonical to alternative E-box sequences and regulating myomiRs expression. SNAIL silencing allows the re-expression of MYF5 and canonical MYOD binding, promoting RMS cell myogenic differentiation. These novel results open potential avenues for the development of innovative therapeutic strategies based on SNAIL silencing.
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Project description:Dysregulation of the proteostasis network is associated with various diseases including cancer. Previous studies have shown that inhibiting components of this network, such as HSP70 chaperones, can selectively induce cell death in rhabdomyosarcoma (RMS), a common pediatric soft tissue sarcoma. Here we show that inhibiting VCP, an ATPase involved in protein degradation, activates the unfolded protein response and induces apoptosis in RMS, with a preclinical p97 inhibitor showing promising anti-tumor activity in mouse models. The findings confirm the efficacy of targeting the proteostasis network in RMS and suggest that targeting compensatory network components might yield synergistic outcomes.
2025-06-24 | GSE270783 | GEO
Project description:We have recently reported the down-regulation of pannexin 1 (PANX1) levels in rhabdomyosarcoma (RMS) and that restoration of its expression inhibits the progression of embryonal (eRMS) and alveolar (aRMS) rhabdomyosarcoma in vitro and in vivo. While we have shown that this PANX1-mediated inhibition of RMS progression involves reduction of cell proliferation and migration, as well as induction of apoptosis, the underlining molecular mechanisms at play remained to be elucidated. In the present study, using RNA sequencing (RNA-seq) combined with DAVID analysis, we identified the PANX1 interactome in RMS cells and showed that the Gene Ontology (GO) terms such as apoptosis and migration, and KEGG pathways such as MAPK and Rap1 Signaling pathways were amongst the most highly enriched processes in Rh30 (aRMS) cells expressing ectopic PANX1. We then used a proximity-dependent labeling approach (BioID) to screen for the PANX1 interactors in RMS cells, which was complemented by co-immunoprecipitation (co-IP) coupled to high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) performed using Myc-PANX1-enriched subcellular fractions. STRING protein network analyses of the overlapping hits from these two approaches revealed a PANX1 interactome with plasma membrane and cytoskeleton associated proteins from which ACTB and AHNAK were further validated by co-IP using whole cell lysates followed by Western blotting analysis. Using this new and comprehensive information, we have generated the first online PANX1 transcriptome and interactome databases that allow searching, in a user-friendly manner, for PANX1-regulated genes and PANX1 interactors. Moreover, AHNAK knockdown in PANX1-expressing Rh18 (eRMS) and Rh30 (aRMS) significantly abrogated the PANX1-mediated reduction in cell viability and migration, as well as the PANX1-mediated sensitivity to anoikis. Using a combination of genome-wide unbiased approaches, this study is thus the first to identify the PANX1 transcriptome and interactome, providing the research community with online searchable databases to access the PANX1-regulated genes and PANX1 interacting partners. We have shown that PANX1 interacts with AHNAK and that this interaction is critical to the PANX1-mediated inhibition of RMS cell viability and migration, and induction of apoptosis; thus demonstrating how this new information can be used to identify key members of the PANX1 signaling pathway and their relevance to PANX1 function.
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Project description:Rhabdomyosarcoma (RMS) is a pediatric soft tissue cancer with no precision therapy available for affected patients. We hypothesized that with a general paucity of known mutations in RMS, chromatin structural driving mechanisms are essential for tumor proliferation. Thus, we carried out high-depth in situ Hi-C in representative cell lines and patient-derived xenografts to understand chromatin architecture in each major RMS subtype. We report a comprehensive 3D chromatin structural analysis and characterization of fusion-positive (FP-RMS) and fusion-negative rhabdomyosarcoma (FN-RMS). We have generated spike-in in situ Hi-C chromatin interaction maps for the commonest FP-RMS and FN-RMS cell lines, and compared our data with patient derived xenograft (PDX) models. In our studies we uncover common and distinct structural elements in large Mb-scale chromatin compartments, tumor-essential genes within variable topologically associating domains, and unique patterns of structural variation. This study enables a comprehensive resource for contextualizing gene regulation events in RMS, and high-depth chromatin interactivity maps for identification of functionally critical chromatin domains in this tumor.
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