Investigating Novel Functions for NIK/MAP3K14 in High-Grade Glioma

项目摘要 癌细胞能够适应在有限的环境中不受控制地和侵入性地生长 营养物质--最显著的是葡萄糖和氧气。事实上，高海拔地区的侵略性迁移和入侵- 包括多形性胶质母细胞瘤（GBM）在内的分级胶质瘤进入健康脑组织是主要因素 导致这种恶性肿瘤的治疗抗性和不良预后。虽然许多癌细胞 尽管GBM细胞优先利用糖酵解来支持生长，但已经显示GBM细胞依赖于糖酵解和糖代谢两者， 线粒体代谢葡萄糖能量利用。线粒体动力学，或者说 线粒体的分裂和融合是生物能量适应细胞应激的中心机制 例如营养缺乏。因此，靶向失调的线粒体功能是一种非常有吸引力的方法。 GBM的治疗策略最近的研究结果表明，NF-κ B诱导激酶 (NIK/MAP 3 K14）在调节线粒体动力学和亚细胞运输以促进细胞增殖中的作用。 GBM细胞的侵袭性和发病机制。此外，初步数据表明， NIK通过调节线粒体膜电位增强GBM细胞对营养/葡萄糖饥饿的抵抗力 新陈代谢.此外，NIK的线粒体作用不依赖于其对NF-κB活性的调节。 然而，NIK协调线粒体功能调节的分子机制， GBM细胞中的代谢重编程目前尚不清楚。这一提议检验了NIK的假设， 是由线粒体动力学、癌细胞代谢和细胞周期的重要调节因子， 营养缺乏导致的渗透性生长。该提案的目标是从功能上定义 调节癌细胞线粒体的NIK依赖性调节网络和代谢途径 功能，并测试NIK抑制是否会使GBM细胞对营养饥饿敏感， 肿瘤细胞存活和发病机制。预计这一提议将产生重要的积极影响 因为了解NIK线粒体功能的分子基础可能会产生强大的 开发靶向线粒体的新型、基于机制的GBM疗法的理由 通过NIK抑制功能障碍、侵袭和代谢失调，最终目标是 提高患者生存率。 !

PROJECT SUMMARY Cancer cells are able to adapt to grow uncontrollably and invasively in environments with limited availability of nutrients — most notably, glucose and oxygen. Indeed, the aggressive migration and invasion of high- grade gliomas, including glioblastoma multiforme (GBM), into healthy brain tissue are major factors contributing to the therapy resistance and poor prognosis of this malignancy. While many cancer cells preferentially utilize glycolysis to support growth, GBM cells have been shown to rely on both glycolysis and mitochondrial metabolism for glucose energy utilization. Mitochondrial dynamics, or the balance between mitochondrial fission and fusion, is a central mechanism for bioenergetic adaptations to cellular stresses such as nutrient deprvation. Therefore, targeting de-regulated mitochondrial function is a highly attractive therapeutic strategy for GBM. Recent findings have established key roles for NF-κB-inducing kinase (NIK/MAP3K14) in regulating mitochondrial dynamics and subcellular trafficking to promote the invasiveness and pathogenesis of GBM cells. Moreover, preliminary data demonstrate that mitochondrial NIK enhances the resistance of GBM cells to nutrient/glucose starvation through regulation of mitochondrial metabolism. Moreover, the mitochondrial actions of NIK are independent of its regulation of NF-κB activity. However, the molecular mechanisms by which NIK coordinates regulation of mitochondrial function and metabolic reprogramming in GBM cells are currently not known. This proposal tests the hypothesis that NIK is induced by, and is an important regulator of, mitochondrial dynamics, cancer cell metabolism and infiltrative growth in response to nutrient deprivation. The goals of the proposal are to functionally define NIK-dependent regulatory networks and metabolic pathways that regulate cancer cell mitochondrial functions and test the whether NIK inhibition will sensitize GBM cells to nutrient starvation and attenuate tumor cell survival and pathogenesis. This proposal is anticipated to have an important positive impact because understanding the molecular basis of NIK mitochondrial functions is likely to generate strong justification for the development of novel, mechanism-based therapies for GBM that target mitochondrial dysfunction, invasion, and de-regulated metabolism through NIK inhibition with the ultimate goal of improving patient survival. !