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中文摘要
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自我更新的肿瘤增殖细胞驱动肿瘤持续生长并导致复发。如果这个过程
英文摘要
Self-renewing tumor-propagating cells drive continued tumor growth and are responsible for relapse. If the process by which tumor cells self-renew could be turned off, then tumors would regress and patients would remain relapse free. The goal of this updated proposal is to define the cellular and molecular mechanisms by which Notch regulates tumor-propagating potential and plasticity of the tumor propagating cell state in embryonal rhadomyosarcoma (ERMS), a devastating pediatric malignancy of the muscle. Relapse is the major clinical problem facing patients with ERMS, with less than 40% of relapse patients surviving their disease. Progress on this project using a combination of in vivo experiments in the zebrafish ERMS model and in in vitro experiments using ERMS cell lines and primary tissues has validated the hypothesis that Notch pathway activation increases the pool of tumor- propagating cells (TPCs), but rather surprisingly in vivo cell transplantation experiments finds that Notch enables the dedifferentiation of non-TPCs into TPCs. Using human patient samples, ERMS cell lines and correlative data in zebrafish has identified critical Notch regulated targets in human ERMS including SNAI1, MEF2C, PAX7 and MYF5. Preliminary data within my proposal shows that RAS-driven ERMS contain a molecularly distinct population of ERMS-propagating cells that express high levels of myf5 but lack differentiated muscle marker expression. These cells can be directly visualized in live, fluorescent- transgenic zebrafish, allowing unprecedented access to visualize self-renewal in live animals. Building on these observations, my proposal will determine the cellular and molecular mechanisms by which Notch alters tumor-propagating potential in both zebrafish and human ERMS. Specifically, Aim 1 will assess if Notch pathway activation alters symmetric vs. asymmetric divisions in the ERMS-propagating cell subfraction by dynamic real-time imaging of live, fluorescent transgenic fish. A sub aim will use lineage tracing methods to define the frequency and dynamics of dedifferentiation to make TPCs in ERMS. Aim 2 Will show that NOTCH1 expands TPCs in vivo in human ERMS by utilizing limiting dilution cell transplantation of low passage human primary ERMS cells into immune compromised mice. Aim 3 will assess the molecular mechanisms by which downstream NOTCH1 effector genes SNAI1, PAX7, MYF5 and MEF2C expands self-renewal, drives dedifferentiation and blocks terminal differentiation. In total, my proposal provides a comprehensive strategy to interrogate how the Notch pathway regulates ERMS self- renewal and will likely have immense therapeutic significance as clinically-relevant Notch pathway inhibitors would likely reduce tumor propagating cell frequency, dedifferentiation and ultimately relapse.
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A role for notch in self renewal in embryonal rhabdomyosarcoma
A role for notch in self renewal in embryonal rhabdomyosarcoma
  • 批准号:
    8808736
  • 项目类别:
  • 资助金额:
    $18.04万
  • 财政年份:
    2014
  • 负责人:
    Myron Steve Ignatius
  • 依托单位:
A role for notch in self renewal in embryonal rhabdomyosarcoma
  • 批准号:
    8635072
  • 项目类别:
  • 资助金额:
    $18.04万
  • 财政年份:
    2014
  • 负责人:
    Myron Steve Ignatius
  • 依托单位:
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