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.

项目概要 所有干细胞都具有自我更新的能力，能够在不分化的情况下产生子代干细胞 干细胞从其微环境中接收信号，指示它们自我更新和预防。 它们通过一系列细胞器间通讯过程进行区分。 最近发现，胶质母细胞瘤是最常见和致命的脑肿瘤类型，其“根源”在于 与神经干细胞不同，神经胶质瘤干细胞（GSC）群具有无穷无尽的自我更新能力。 细胞（NSC）、GSC 也能够在它们遇到的次优环境中维持其干性 在入侵过程中，GSC（而非 NSC）如何能够在其生态位之外保持其干性。 为了确定影响 GSC 和生态位相互作用的潜在神经胶质瘤抑制因子，我们 发现 RNA 结合蛋白 Quaking (QKI) 是控制受体的内吞作用的关键调节因子 从机制上讲，QKI 调节 mRNA 前体的稳定性。 调节内溶酶体脂质成分的基因，特别是不饱和脂肪酸（UFA）。 内溶酶体功能缺陷的后果，我们发现 QKI 的消耗和 UFA 的抑制 生物合成导致细胞质膜结合受体的富集，这是维持 此外，由于多不饱和脂肪酸（PUFA）是铁死亡的底物， 由于 Qki 缺失而导致 PUFA 下调，使得 GSC 对铁死亡（一种主要的肿瘤抑制）具有抵抗力 支持 QKI 和 UFA 调节的细胞内囊泡运输系统的重要性。 在胶质母细胞瘤的生物合成中，我们发现 QKI、内溶酶体和硬脂酰辅酶 A 去饱和酶水平较低 （SCD，UFA 生物合成的关键酶）均与胶质母细胞瘤较差的预后显着相关 我们的长期目标是开发针对有缺陷的内溶酶体功能的疗法。 鉴于 QKI 是 SCD 基因的主要调节因子并抑制 QKI 和 UFA 生物合成。 可以损害内溶酶体活性并促进神经胶质瘤发生，我们勇敢地说 QKI 缺失/突变 通过下调 UFA 生物合成和恢复来破坏 NSC 和 GSC 的内溶酶体功能 PUFA 水平可以使肿瘤细胞对铁死亡敏感。为了检验这一假设，我们将 (a) 确定其作用。 NSC 和 GSC 中 QKI 调节的内溶酶体功能中 Scd1/2 介导的 UFA 生物合成，(b) 澄清 QKI 在 NSC 和 GSC 中调节 Scd1/2 前体 mRNA 稳定性的机制，以及 (c) 评估 这些研究将共同​​探讨恢复 PUFA 水平对肿瘤细胞铁死亡敏感的影响。 阐明胶质瘤抑制因子 QKI 如何调节细胞内囊泡运输的分子机制 通过脂质代谢在 NSCs 和 GSCs 中发挥作用，更重要的是，它们将有助于 专门针对 QKI/SCD 耗尽的胶质母细胞瘤的治疗策略。