The role of membrane homoeostasis of neural stem cell and glioma stem cells in neural development and gliomagenesis

神经干细胞和胶质瘤干细胞膜稳态在神经发育和胶质瘤发生中的作用

• 批准号: 10713009
• 负责人: Jian Hu
• 金额: $ 41.76万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10713009
• 关键词: Affect; Agonist; Alternative Splicing; Brain Neoplasms; Cell membrane; Cells; Communication; Complement; Data; Daughter; Down-Regulation; Endocytosis; Environment; Enzymes; Fatty Acids; Gene Expression; Genes; Glioblastoma; Glioma; Gliomagenesis; Goals; Heterogeneous-Nuclear Ribonucleoprotein L; Human; Immune; Impairment; In Vitro; Invaded; Lipids; Mediating; Membrane; Molecular; Mus; Mutate; Mutation; Neurophysiology - biologic function; Organelles; Outcome; PPAR-beta; Pathway interactions; Patients; Polyunsaturated Fatty Acids; Population; Process; Prognosis; Proteins; RNA; RNA Stability; RNA-Binding Proteins; Resistance; Role; Signal Transduction; Stearoyl-CoA Desaturase; System; Testing; Therapeutic; Therapeutic Effect; Tumor Suppression; Unsaturated Fatty Acids; Vesicle; Work; cell type; desensitization; fatty acid biosynthesis; flexibility; fluidity; in vivo; lipid metabolism; mRNA Precursor; mRNA Stability; migration; neoplastic cell; nerve stem cell; neurodevelopment; novel therapeutic intervention; novel therapeutics; pi bond; prevent; receptor; receptor binding; response; restoration; self-renewal; stem cell self renewal; stem cells; stemness; targeted treatment; therapeutic development; therapy development; trafficking

PROJECT SUMMARY All stem cells have the capacity for self-renewal, an ability to create daughter stem cells without differentiating into other cell types. Stem cells receive the signals from their niches that instruct them to self-renew and prevent them from differentiating through a cascade of inter-organelle communication processes. Substantial evidence has recently revealed that glioblastoma, the most common and lethal type of brain tumor, has “roots” in a population of glioma stem cells (GSCs) that possess an inexhaustible ability to self-renew. Unlike neural stem cells (NSCs), GSCs are also able to sustain their stemness in the suboptimal environments they encounter outside their niches during invasion. How GSCs, but not NSCs, are able to maintain their stemness outside the niches remains unclear. To identify potential glioma suppressors that affect interaction of GSCs and niches, we discovered that RNA-binding protein Quaking (QKI) is a key regulator of endocytosis that controls receptor trafficking, degradation, and signaling desensitization. Mechanistically, QKI regulates pre-mRNA stability of genes that regulate lipid components of endolysosomes, particularly the unsaturated fatty acids (UFAs). As a consequence of defective endolysosomal function, we showed that depletion of QKI and inhibition of UFA biosynthesis led to the enrichment of cytoplasmic membrane-bound receptors that are required for maintaining stemness. In addition, since polyunsaturated fatty acids (PUFAs) are the substrates of ferroptosis, downregulation of PUFA due to Qki loss renders GSCs resistant to ferroptosis, a major tumor suppression mechanism. Supporting the importance of intracellular vesicle trafficking system regulated by QKI and UFA biosynthesis in glioblastoma, we found that lower levels of QKI, endolysosome and Stearoyl-CoA desaturase (SCD, the key enzyme for UFA biosynthesis) all correlate significantly with poorer prognosis in glioblastoma patients. Our long-term goal is to develop therapies that target the defective endolysosome function in glioblastoma. Given that QKI is a major regulator of SCD genes and inhibition of both QKI and UFA biosynthesis can impair the endolysosome activity and promote gliomagenesis, we hypothesize that QKI deletions/mutations disrupt endolysosomal function in NSCs and GSCs through downregulation of UFA biosynthesis and restoration of PUFA levels can sensitize tumor cells to ferroptosis. To test this hypothesis, we will (a) determine the role of Scd1/2-mediated UFA biosynthesis in QKI-regulated endolysosome functions in both NSCs and GSCs, (b) clarify the mechanism by which QKI regulates Scd1/2 pre-mRNA stability in both NSCs and GSCs, and (c) evaluate the effects of restoration of PUFA levels in sensitizing tumor cells to ferroptosis. Together, these studies will elucidate the molecular mechanisms of how the glioma suppressor QKI regulates intracellular vesicle trafficking in NSCs and GSCs through lipid metabolism, and more importantly, they will contribute to the development of therapeutic strategies that specifically target QKI/SCD-depleted glioblastoma.

项目摘要 所有干细胞都具有自我更新的能力，能够创建子干细胞而无需区分的能力 进入其他细胞类型。干细胞从其利基市场接收信号，这些信号指示他们自我更新并防止 他们通过一系列轨道间通信过程来区分。大量证据 最近透露，胶质母细胞瘤是最常见和致命类型的脑肿瘤，在A中具有“根” 胶质瘤干细胞（GSC）的种群潜在自我更新的能力。与神经茎不同 细胞（NSC），GSC也能够在遇到的次优环境中维持其干性 入侵期间的利基市场。 GSC（而不是NSC）如何在外面保持其茎 利基仍然不清楚。为了确定影响GSC和壁ni的相互作用的潜在神经胶质瘤补充剂，我们 发现RNA结合蛋白Quaking（QKI）是控制接收器的内吞作用的关键调节剂 贩运，退化和信号脱敏。从机械上讲，QKI调节了前MRNA的稳定性 调节内溶性溶肿的脂质成分的基因，特别是不饱和脂肪酸（UFAS）。作为 内溶性功能有缺陷的结果，我们表明QKI的耗竭和抑制UFA 生物合成导致维持所需的细胞质膜结合接收器的富集 茎。另外，由于多不饱和脂肪酸（PUFAS）是铁肉芽症的底物，所以 由于QKI损失引起的PUFA的下调使GSC具有抗铁毒性的GSC，这是一种主要的肿瘤抑制 机制。支持受QKI和UFA调节的细胞内囊泡运输系统的重要性 胶质母细胞瘤的生物合成，我们发现Qki，内溶液体和stearoyl-COA去饱和酶的水平较低 （SCD，UFA生物合成的关键酶）都与胶质母细胞瘤的预后较差显着相关 患者。我们的长期目标是开发针对有缺陷的内溶性功能功能的疗法 胶质母细胞瘤。鉴于QKI是SCD基因的主要调节剂，并且抑制QKI和UFA生物合成 会损害内溶性活性并促进神经胶质作用，我们假设QKI缺失/突变 通过下调UFA生物合成和恢复，在NSC和GSC中破坏内溶性功能 PUFA水平可以感觉到肿瘤细胞会导致肿瘤病。为了检验这一假设，我们将（a）确定 NSC和GSC中QKI调节的内溶性函数中的SCD1/2介导的UFA生物合成，（b）澄清 QKI调节NSC和GSC中SCD1/2前MRNA稳定性的机制，以及（c）评估 PUFA水平恢复在使肿瘤细胞对铁凋亡敏化的影响。这些研究将在一起 阐明神经胶质瘤抑制剂QKI调节细胞内囊泡运输的分子机制 在NSC和GSC中，通过脂质代谢，更重要的是，它们将有助于发展 专门针对QKI/SCD缺失的胶质母细胞瘤的治疗策略。