Sonic hedgehog fusion-negative rhabdomyosarcoma orgiginates from endothelial progenitors
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE98059 | GEO | 2018/01/25
REPOSITORIES: GEO
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Project description:To further examine the consequences of Pten loss in a Hedgehog driven, murine FN-RMS, we used microarrays to determine the transcriptomic differences between our aP2-Cre;SmoM2 FN-RMS model (Hatley et al. 2012, Cancer Cell) and aP2-Cre; SmoM2; Pten flox/flox FN-RMSs.
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Project description:Fusion-negative rhabdomyosarcoma (FN-RMS) is the most common soft tissue sarcoma of childhood arising from undifferentiated skeletal muscle cells. Tumor cells derived from genetically engineered murine models are a valid tool to study cancer biology. In order to investigate the poor myogenic commitment of FN-RMS, we performed RNA sequencing of two cell lines derived from a previously described genetically engineered murine model of FN-RMS. We then performed bioinformatics analysis to compare the transcriptome with murine satellite cells, and identify the key factors that distinguish FN-RMS from skeletal muscle cells.
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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.
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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.
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Project description:Rhabdomyosarcoma (RMS) is a pediatric malignancy of mesenchymal origin. Fusion Negative-RMS (FN-RMS) tumors are associated with RAS-pathway activation. RMS tumors express pro-differentiation myogenic transcription factors MYOD and MYOG, yet why they are unable to differentiate is poorly understood. Here we show that SNAI2 is highly expressed in FN-RMS, is regulated by MYOD and blocks myogenic differentiation promoting growth. Molecularly, SNAI2 preferentially binds E-Box-associated enhancer elements and represses expression by dampening enhancer function. SNAI2 inhibits MYOD at a subset of myogenic enhancers associated with terminal differentiation. Functional dissection demonstrates SNAI2 suppresses a MYOG, MEF2 and CDKN1A differentiation program. SNAI2 knockdown transcriptionally mimics a chemical blockade of the mutant RAS signal in FN-RMS, providing new insight connecting the genetic and epigenetic causes of this disease.
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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.
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Project description:Rhabdomyosarcoma (RMS) is a pediatric mesenchymal-derived malignancy encompassing Fusion Positive (FP)-RMS expressing PAX3/7-FOXO1 and Fusion Negative (FN)-RMS often mutated in the RAS pathway. RMS expresses the master myogenic transcription factor MYOD that, paradoxically, is unable to support differentiation while essential for tumor cell survival. We identify here SKP2, an oncogenic E3-ubiquitin ligase, as a critical driver of tumorigenesis in FN-RMS. SKP2 is overexpressed in RMS at the highest levels among several adult and pediatric cancers and its expression is maintained by MYOD through an intronic enhancer within the gene. In FN-RMS SKP2 promotes cell cycle progression and prevents differentiation directly targeting p27Kip1 and p57Kip2, respectively, unlocking a transcriptional myogenic program, partly MYOD-dependent, resulting in de novo expression of terminal muscle differentiation markers. SKP2 depletion strongly affects stemness and tumorigenic features in vitro and prevents in vivo tumor growth. The in vitro effects are mirrored by the SKP2 inhibitor SMIP004. Moreover, the investigational NEDDylation inhibitor MLN4924 hampers SKP2 functions restraining FN-RMS cell survival and tumor growth. Our results uncover a MYOD-SKP2 axis crucial for the crosstalk between transcriptional and post-translational mechanisms that contribute to FN-RMS tumorigenesis and broaden the understanding of MYOD function. Furthermore, they suggest inhibition of NEDDylation as a potential therapeutic approach in this tumor.
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Project description:Rhabdomyosarcoma (RMS) is a pediatric mesenchymal-derived malignancy encompassing Fusion Positive (FP)-RMS expressing PAX3/7-FOXO1 and Fusion Negative (FN)-RMS often mutated in the RAS pathway. RMS expresses the master myogenic transcription factor MYOD that, paradoxically, is unable to support differentiation while essential for tumor cell survival. We identify here SKP2, an oncogenic E3-ubiquitin ligase, as a critical driver of tumorigenesis in FN-RMS. SKP2 is overexpressed in RMS at the highest levels among several adult and pediatric cancers and its expression is maintained by MYOD through an intronic enhancer within the gene. In FN-RMS SKP2 promotes cell cycle progression and prevents differentiation directly targeting p27Kip1 and p57Kip2, respectively, unlocking a transcriptional myogenic program, partly MYOD-dependent, resulting in de novo expression of terminal muscle differentiation markers. SKP2 depletion strongly affects stemness and tumorigenic features in vitro and prevents in vivo tumor growth. The in vitro effects are mirrored by the SKP2 inhibitor SMIP004. Moreover, the investigational NEDDylation inhibitor MLN4924 hampers SKP2 functions restraining FN-RMS cell survival and tumor growth. Our results uncover a MYOD-SKP2 axis crucial for the crosstalk between transcriptional and post-translational mechanisms that contribute to FN-RMS tumorigenesis and broaden the understanding of MYOD function. Furthermore, they suggest inhibition of NEDDylation as a potential therapeutic approach in this tumor.
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