Transcriptome analysis of genetically engineered murine fusion-negative rhabdomyosarcoma model-derived cell lines
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE175816 | GEO | 2021/05/31
REPOSITORIES: GEO
Similar Datasets
Project description:Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood and is comprised of two major molecular subtypes. Despite sharing features with skeletal muscle, the conservation of underlying cellular hierarchy with human muscle development and the identification of molecularly-defined tumor-propagating cells have not been reported. Using single-cell RNA sequencing of patient-derived RMS, DNA-barcode cell fate mapping, and antibody enrichment and functional stem cell assays using in vitro culture and mouse xenografts, we have uncovered tumor cell hierarchies in Fusion-negative (FN-) RMS that are shared with normal human muscle development. We also identified common developmental stages at which tumor cells become arrested. FN-RMS resemble early muscle found in embryonic and larval development, while fusion-positive (FP-)RMS express a highly specific developmental gene program found in muscle cells transiting from embryonic to fetal development at 7-7.75 weeks of age. FP-RMS also have neural-pathway enriched cell states, suggesting less-rigid adherence to muscle development hierarchies in this disease. Finally, we identify a molecularly-defined tumor-propagating cell in FN-RMS that shares remarkable similarity to the newly described bi-potent, muscle mesenchyme stem/progenitor cell that makes both muscle and osteogenic cells.
2022-02-05 | GSE195709 | GEO
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:Sarcomas are derailed in pathways that specify mesenchymal lineages during embryogenesis, causing tumor cells to stall at early stages of differentiation. Among them, rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma of skeletal muscle origin. A key feature of RMS is their inability to terminally differentiate despite the high expression of master myogenic regulator MYOD. The bHLH transcription factor TWIST2, which governs mesenchymal stem cell identity and restricts myogenesis, is overexpressed in patient fusion-negative RMS (FN-RMS) tumors. We show that knockdown of TWIST2 enables FN-RMS cells to exit the cell cycle and undergo myogenic differentiation, thereby reducing the growth of FN-RMS xenograft tumors. ChIP-seq analysis revealed that most TWIST2-mediated gene regulation occurs independent of changes in MYOD binding in FN-RMS cells. Instead, TWIST2 controls the deposition of H3K27 acetylation at distal enhancers by interacting with the chromatin remodelers, SMARCA4 and CHD3, to activate growth-related and repress myogenesis-related TWIST2 target genes. Our findings provide new insights into the role of TWIST2 in maintaining an undifferentiated and tumorigenic state of FN-RMS and highlight the clinical potential of reversing the TWIST2-regulated phenotype.
2023-03-20 | GSE207165 | GEO
Project description:Sarcomas are derailed in pathways that specify mesenchymal lineages during embryogenesis, causing tumor cells to stall at early stages of differentiation. Among them, rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma of skeletal muscle origin. A key feature of RMS is their inability to terminally differentiate despite the high expression of master myogenic regulator MYOD. The bHLH transcription factor TWIST2, which governs mesenchymal stem cell identity and restricts myogenesis, is overexpressed in patient fusion-negative RMS (FN-RMS) tumors. We show that knockdown of TWIST2 enables FN-RMS cells to exit the cell cycle and undergo myogenic differentiation, thereby reducing the growth of FN-RMS xenograft tumors. ChIP-seq analysis revealed that most TWIST2-mediated gene regulation occurs independent of changes in MYOD binding in FN-RMS cells. Instead, TWIST2 controls the deposition of H3K27 acetylation at distal enhancers by interacting with the chromatin remodelers, SMARCA4 and CHD3, to activate growth-related and repress myogenesis-related TWIST2 target genes. Our findings provide new insights into the role of TWIST2 in maintaining an undifferentiated and tumorigenic state of FN-RMS and highlight the clinical potential of reversing the TWIST2-regulated phenotype.
2023-03-20 | GSE207168 | GEO
Project description:Sarcomas are derailed in pathways that specify mesenchymal lineages during embryogenesis, causing tumor cells to stall at early stages of differentiation. Among them, rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma of skeletal muscle origin. A key feature of RMS is their inability to terminally differentiate despite the high expression of master myogenic regulator MYOD. The bHLH transcription factor TWIST2, which governs mesenchymal stem cell identity and restricts myogenesis, is overexpressed in patient fusion-negative RMS (FN-RMS) tumors. We show that knockdown of TWIST2 enables FN-RMS cells to exit the cell cycle and undergo myogenic differentiation, thereby reducing the growth of FN-RMS xenograft tumors. ChIP-seq analysis revealed that most TWIST2-mediated gene regulation occurs independent of changes in MYOD binding in FN-RMS cells. Instead, TWIST2 controls the deposition of H3K27 acetylation at distal enhancers by interacting with the chromatin remodelers, SMARCA4 and CHD3, to activate growth-related and repress myogenesis-related TWIST2 target genes. Our findings provide new insights into the role of TWIST2 in maintaining an undifferentiated and tumorigenic state of FN-RMS and highlight the clinical potential of reversing the TWIST2-regulated phenotype.
2023-03-20 | GSE207167 | GEO
Project description:Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma occurring in the pediatric population, arises from the skeletal muscle compartment. Several transcriptional and post-transcriptional regulators lock the tumor in a continuous undifferentiated state and prevent the cells from returning to quiescence. MicroRNAs (miRNAs) are short non-coding RNAs that modulate cell identity by means of post-transcriptional regulation of messenger RNAs. In this study, we aimed at identifying miRNAs that could affect FN-RMS cell identity. Thus, we analyzed publicly available datasets and identified miR-449a and miR-340 as the main regulators of cell cycle and p53 signaling. Using miR-eCLIP technology, we identified the direct effects of miRNAs in FN-RMS cell lines, and an overall rewiring of cell identity at the transcriptomic, epigenetic and metabolic level. We observed that miR-449a+340 directly and indirectly targeted glycolysis and pyruvate entry into mitochondria by inhibiting mitochondrial pyruvate complex (MPC) inhibition. The pharmacological inhibition of MPC resulted in a similar metabolic shift with cell cycle exit and a significant reduction in metastatic potential of FN-RMS models. In conclusion, the combination of miR-449 and miR-340 play a pivotal role in orchestrating the cell identity of FN-RMS, and the modulation of MPC emerges as a key factor in redirecting FN-RMS towards a quiescent, non-tumorigenic state.
2024-09-03 | GSE275736 | GEO
Project description:Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma occurring in the pediatric population, arises from the skeletal muscle compartment. Several transcriptional and post-transcriptional regulators lock the tumor in a continuous undifferentiated state and prevent the cells from returning to quiescence. MicroRNAs (miRNAs) are short non-coding RNAs that modulate cell identity by means of post-transcriptional regulation of messenger RNAs. In this study, we aimed at identifying miRNAs that could affect FN-RMS cell identity. Thus, we analyzed publicly available datasets and identified miR-449a and miR-340 as the main regulators of cell cycle and p53 signaling. Using miR-eCLIP technology, we identified the direct effects of miRNAs in FN-RMS cell lines, and an overall rewiring of cell identity at the transcriptomic, epigenetic and metabolic level. We observed that miR-449a+340 directly and indirectly targeted glycolysis and pyruvate entry into mitochondria by inhibiting mitochondrial pyruvate complex (MPC) inhibition. The pharmacological inhibition of MPC resulted in a similar metabolic shift with cell cycle exit and a significant reduction in metastatic potential of FN-RMS models. In conclusion, the combination of miR-449 and miR-340 play a pivotal role in orchestrating the cell identity of FN-RMS, and the modulation of MPC emerges as a key factor in redirecting FN-RMS towards a quiescent, non-tumorigenic state.
2024-09-03 | GSE275735 | GEO
Project description:Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma occurring in the pediatric population, arises from the skeletal muscle compartment. Several transcriptional and post-transcriptional regulators lock the tumor in a continuous undifferentiated state and prevent the cells from returning to quiescence. MicroRNAs (miRNAs) are short non-coding RNAs that modulate cell identity by means of post-transcriptional regulation of messenger RNAs. In this study, we aimed at identifying miRNAs that could affect FN-RMS cell identity. Thus, we analyzed publicly available datasets and identified miR-449a and miR-340 as the main regulators of cell cycle and p53 signaling. Using miR-eCLIP technology, we identified the direct effects of miRNAs in FN-RMS cell lines, and an overall rewiring of cell identity at the transcriptomic, epigenetic and metabolic level. We observed that miR-449a+340 directly and indirectly targeted glycolysis and pyruvate entry into mitochondria by inhibiting mitochondrial pyruvate complex (MPC) inhibition. The pharmacological inhibition of MPC resulted in a similar metabolic shift with cell cycle exit and a significant reduction in metastatic potential of FN-RMS models. In conclusion, the combination of miR-449 and miR-340 play a pivotal role in orchestrating the cell identity of FN-RMS, and the modulation of MPC emerges as a key factor in redirecting FN-RMS towards a quiescent, non-tumorigenic state.
2024-09-03 | GSE275734 | GEO
Project description:Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma occurring in the pediatric population, arises from the skeletal muscle compartment. Several transcriptional and post-transcriptional regulators lock the tumor in a continuous undifferentiated state and prevent the cells from returning to quiescence. MicroRNAs (miRNAs) are short non-coding RNAs that modulate cell identity by means of post-transcriptional regulation of messenger RNAs. In this study, we aimed at identifying miRNAs that could affect FN-RMS cell identity. Thus, we analyzed publicly available datasets and identified miR-449a and miR-340 as the main regulators of cell cycle and p53 signaling. Using miR-eCLIP technology, we identified the direct effects of miRNAs in FN-RMS cell lines, and an overall rewiring of cell identity at the transcriptomic, epigenetic and metabolic level. We observed that miR-449a+340 directly and indirectly targeted glycolysis and pyruvate entry into mitochondria by inhibiting mitochondrial pyruvate complex (MPC) inhibition. The pharmacological inhibition of MPC resulted in a similar metabolic shift with cell cycle exit and a significant reduction in metastatic potential of FN-RMS models. In conclusion, the combination of miR-449 and miR-340 play a pivotal role in orchestrating the cell identity of FN-RMS, and the modulation of MPC emerges as a key factor in redirecting FN-RMS towards a quiescent, non-tumorigenic state.
2024-11-27 | GSE282611 | GEO
Project description:We have developed a new conditional genetically engineered mouse model of rhabdomyosarcoma (RMS) with homologous molecular signature to human RMS that provides valuable pre-clinical models for evaluating novel therapies
2022-02-04 | GSE195922 | GEO