Pathway-Specific NF-kappaB Regulatory Networks in Glioma

描述（由申请人提供）：高级别胶质瘤是所有类型人类癌症中最严重的肿瘤之一，目前治疗的疗效仍然很差。我们感兴趣的是NF-κB转录因子家族作为神经胶质瘤肿瘤干细胞（CSC）的关键调节因子的作用，这被认为是引起肿瘤细胞异质性和侵袭性生长的原因。迄今为止，抗NF-κB癌症治疗策略集中于靶向经典NF-κB（RelA/IKK α）活化，而不考虑非经典NF-κB通路（RelB/IKKα）。基于我们最近的发现，即RelB促进间充质胶质瘤的肿瘤发生（Lee et al. PLOS One，2013），我们认为迫切需要了解特定的NF-κB信号通路如何促进肿瘤的发生/进展。具体来说，我们认为经典和非经典NF-κB信号可能在不同的胶质瘤亚型以及不同的癌症干细胞群体中特别重要。近年来的研究表明，转化生长因子β（TGF β）诱导的上皮细胞向间质细胞转化（EMT）与肿瘤干细胞的存活和侵袭密切相关。然而，EMT和CSC存活在胶质瘤中的作用尚不清楚。基于初步数据，我们建议：1）确定哪些NF-κB蛋白和上游信号通路在不同的胶质瘤亚型和CSC中被激活; 2）评估特定NF-κB蛋白在不同CSC群体中促进自我更新和多能性的作用; 3）测试抑制IKK/NF-κB对胶质瘤CSC存活、侵袭和肿瘤生长的影响。更好地理解调节胶质瘤干细胞自我更新和分化的机制不仅将揭示胶质瘤肿瘤生物学的新见解，而且还将有助于确定靶向负责肿瘤异质性和治疗抗性的关键细胞的新方法。

DESCRIPTION (provided by applicant): High-grade gliomas have one of worst prognoses among all types of human cancers and the efficacy of current therapies remains poor. We are interested in the role of the NF-κB transcription factor family as a key regulator of glioma cancer stem cells (CSCs), which are proposed to give rise to tumor cell heterogeneity and invasive growth. To-date, anti-NF-κB cancer therapy strategies have focused on targeting canonical NF-κB (RelA/IKKß) activation without consideration of the non-canonical NF-κB pathway (RelB/IKKα). Based on our recent findings that RelB promotes oncogenesis in mesenchymal glioma (Lee et al. PLOS One, 2013), we argue that there is a critical need to understand how specific NF-κB signaling pathways contribute to tumor initiation/ progression. Specifically, we propose that canonical and non-canonical NF-κB signaling may be particularly important in different glioma subtypes, as well as distinct cancer stem cell populations. Recent studies suggest an intimate relationship between transforming growth factor ß (TGFß)-induced epithelial-to-mesenchymal transition (EMT) and CSCs survival and invasion. However, the role of EMT and CSC survival in glioma is unclear. Based on preliminary data, we propose to 1) determine which NF-κB proteins and upstream signaling pathways are activated in different glioma subtypes and CSCs; 2) evaluate the role of specific NF-κB proteins in promoting self-renewal and pluripotency in distinct CSC populations; and 3) test the effects of inhibiting IKK/NF-κB on glioma CSC survival, invasion and tumor growth in vivo. A better understanding of the mechanisms regulating glioma stem-cell self-renewal and differentiation will not only reveal new insights into glioma tumor biology, but will also facilitate identifying novel approache to target the key cells responsible for tumor heterogeneity and treatment resistance.