Hypoxia Regulates Notch Turnover in Glioma Stem Cells Through Vasorin

 描述(由申请人提供)：癌症干细胞存在于缺氧区，有助于肿瘤的进展。这些细胞特别难治疗，因为它们天生对常规治疗具有抵抗力，而且它们的微环境降低了放射的疗效，损害了化疗的交付。胶质母细胞瘤是一种以缺氧区为特征的无法治愈的原发脑肿瘤。Notch信号将GSCs维持在低氧的生态位内，但Notch是如何调节失调的尚不清楚。我们的初步数据强烈表明，低氧可以调节细胞膜Notch水平，从而调节受体对配体结合的可用性。我们发现，最近发现的低氧调节蛋白Vasorin在GSCs中优先表达，以调节Notch信号。我们的数据表明，Vasorin通过抑制Notch1的溶酶体降解来调节GSC的自我更新。因此，我们已经确定了一种新的低氧引导Notch信号的机制：调节受体周转。我们的中心假设是，Vasorin通过调节Notch信号来调节缺氧生态位内GSC的自我更新，靶向Vasorin可能会改善GBM的治疗。我们将通过机械学和临床前研究来检验我们的假设。在目标1中，我们将确定Vasorin在体内外介导GSC特性和致瘤潜能中的作用。在目标2中，我们将明确Vasorin在调节Notch信号以促进GSC在低氧条件下自我更新中的作用。在目标3中，我们将评估Vasorin作为一个预后生物标志物，并提供原则证明，通过双靶向Vasorin和Notch蛋白分解处理最大化Notch抑制可以提高小鼠胶质母细胞瘤模型的存活率。重要的是，Vasorin似乎不在正常胚胎或成人脑中表达。因此，以血管紧张素转换酶为靶点可能具有有限的正常脑毒性。这些数据将揭示Vasorin在调节Notch信号中的重要作用，并具有重要的临床意义。目前使用低氧调节剂或Notch途径抑制剂的治疗方法，如分泌酶抑制剂，都受到副作用的限制。如果成功，这项研究的发现将为开发针对Vasorin的新疗法提供强有力的理论基础。

 DESCRIPTION (provided by applicant): Cancer stem cells reside in hypoxic areas and contribute to tumor progression. These cells are particularly difficult to treat because they are inherently resistant to conventional therapy, and their microenvironment reduces the efficacy of radiation and impairs delivery of chemotherapy. Glioblastoma is an incurable primary brain tumor that is characterized by regions of hypoxia. Notch signaling maintains GSCs within the hypoxic niche, but how Notch is dysregulated is unclear. Our preliminary data strongly suggest that hypoxia can regulate membranous Notch levels, thereby regulating receptor availability for ligand binding. We have found that the recently identified hypoxia-regulated protein, Vasorin, is preferentially expressed in GSCs to regulate Notch signaling. Our data suggest that Vasorin regulates GSC self-renewal by inhibiting the lysosomal degradation of Notch1. Thus, we have identified a novel mechanism by which hypoxia directs Notch signaling: regulation of receptor turnover. Our central hypothesis is that Vasorin regulates GSC self-renewal within the hypoxic niche by regulating Notch signaling and that targeting Vasorin may improve GBM therapy. We will test our hypothesis through mechanistic and preclinical studies. In Aim 1, we will determine the role of Vasorin in mediating GSC properties and tumorigenic potential in vitro and in vivo. In Aim 2, we will define the role of Vasorin in regulating Notch signaling to promote GSC self-renewal under hypoxic conditions. In Aim 3, we will assess Vasorin as a prognostic biomarker and provide proof-of-principle that maximizing Notch inhibition by dual targeting of Vasorin and Notch proteolytic processing can improve survival in mouse models of glioblastoma. Importantly, Vasorin does not appear to be expressed in normal embryonic or adult brain. Therefore, targeting Vasorin may have limited normal brain toxicity. These data will reveal an important role for Vasorin in regulating Notch signaling and have significant clinical ramifications. Current therapies using hypoxia modifiers or Notch pathway inhibitors, such as -secretase inhibitors, are limited by side effects. If successful, the findings of this study will provide a strong rationale for the development of novel therapeutics against Vasorin.