Project description:Rhabdomyosarcoma (RMS), the most common paediatric soft-tissue sarcoma, is characterized by cells of skeletal muscle origin that fail to both irreversibly exit the cell cycle and complete skeletal muscle differentiation. Embryonal rhabdomyosarcoma (ERMS) is the most prevalent subtype of RMS and its molecular signatures has been associated with metabolism defects and increased oxidative stress. However, the details of the contributing factors or molecules have not been studied. Both metabolism and oxidative stress are associated with mitochondrial functions and an important molecule that regulates mitochondrial functions is calcium. Till date, there has been no studies that examine the role of mitochondrial calcium in ERMS. In addition, the molecular component of mitochondrial calcium uniporter complex, which is responsible for the uptake of mitochondrial calcium was only discovered in 2012. Since then, there has been an increasing interest in investigating the role of mitochondrial calcium and mitochondrial calcium uniporter complex in various cancers. Mitochondrial calcium uniporter (MCU), the main channel forming protein is often found to be dysregulated in various cancers. Our preliminary data has shown that mitochondrial calcium is dysregulated in ERMS due to overexpression of MCU. This dysregulation of mitochondrial calcium has led to multiple mitochondrial dysfunctions and oncogenic phenotypes. Hence, we would like to investigate the downstream targets of MCU in order to identify the mechanism through which MCU regulates oncogenic phenotypes in ERMS.
Project description:A series of conditional mouse models of embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma and spindle cell sarcoma were generated and validated for relavence to corresponding human cancers. Conditional mouse models of embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma and spindle cell sarcoma were created by activation or deletion of Pax3:Fkhr, p53, Ptch1 or Rb1 genes.
Project description:A series of conditional mouse models of embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma and spindle cell sarcoma were generated and validated for relavence to corresponding human cancers.
Project description:Fluorescent-labeled zebrafish RAS-induced embryonal rhabdomyosarcoma (ERMS) were created to facilitate in vivo imaging of tumor-propagating cells, regional tumor heterogeneity, and dynamic cell movements in diverse cellular compartments. Using this strategy, we have identified a molecularly distinct ERMS cell subpopulation that expresses high levels of myf5 and is enriched for ERMS-propagating potential when compared with other tumor-derived cells. Embryonal rhabdomyosarcoma (ERMS) is an aggressive pediatric sarcoma of muscle. Here, we show that tumor-propagating potential is confined to myf5+ERMS cells and can be visualized in live, fluorescent transgenic zebrafish. During early tumor growth, myf5+ERMS cells reside within an expanded satellite cell compartment, but by late stage ERMS, myf5+cells are dynamically reorganized into distinct regions separated from differentiated tumor cells. Human ERMS also contain distinct areas of differentiated and undifferentiated cells. Time-lapse imaging revealed that myf5+ERMS cells populate newly formed tumor only after seeding by highly migratory myogenin+ ERMS cells. This finding helps explain the clinical observation that Myogenin positivity correlates with poor clinical outcome in human ERMS and suggests that differentiated tumor cells play critical roles in metastasis.
Project description:Embryonal rhabdomyosarcoma (ERMS) is the most common soft tissue cancer in children and is characterized by myogenic differentiation arrest. The prognosis of patients with relapsed or metastatic disease remains poor. ERMS genomes show few recurrent mutations, suggesting that other molecular mechanisms such as epigenetic regulation might play major role in driving ERMS tumor biology. In this study, we have demonstrated the diverse roles of HDACs in the pathogenesis of ERMS by characterizing effects of HDAC inhibitors, trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA; also known as vorinostat) in vitro and in vivo. TSA and SAHA suppress ERMS tumor growth and progression by inducing myogenic differentiation as well as reducing the self-renewal and migratory capacity of ERMS cells. To identify candidate genes that are differentially regulated in histone deacetylase inhibitor-treated embryonal rhabdomyosarcoma, a gene expression profiling study using the Affymetrix Human Gene 2.0 microarray platform and ingenuity pathway analysis of differentially expressed genes were performed on RD and 381T cells treated with trichostatin A or dimethyl sulfoxide (treatment vehicle).
Project description:Affymetrix SNP array data for embryonal rhabdomyosarcoma in a patient with Costello syndrome Affymetrix SNP array was performed according to the manufacturer's directions on DNA extracted from a fresh-frozen tumor sample.
Project description:We report here the analysis of embryonal rhabdomyosarcoma RD cells by transcriptional profiling (bulk RNA-Seq). We use here inducible shRNAs to deplete TRPS1 in RD cells. RD cells were cultured in differentiation medium for 10 days and total RNA was extracted from control or shTRPS1 expressing cells and subjected to RNA-seq.