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.

项目总结