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Role of Quaking gene in regulating the niche-independent stemness of glioma stem cells

Quak基因在调节胶质瘤干细胞的微环境独立干性中的作用

基本信息

批准号：
10310491
负责人：
Jian Hu
金额：
$ 36.6万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10310491
关键词：
Adult Alternative Splicing Animal Model Brain Neoplasms Cell Maintenance Cell membrane Cells Clathrin Complex Consequentialism Cues Data Endocytosis Environment Exons Genes Genetic Glioblastoma Glioma Gliomagenesis Goals Human Knowledge Lead Lysosomes Maintenance Malignant Glioma Mediating Mediator of activation protein Molecular Mutate Neuraxis Numbness Output Pathologic Pathway interactions Pharmacology Plant Roots Play Population Process RNA RNA Splicing RNA-Binding Proteins Receptor Signaling Regulation Role Signal Transduction Testing Therapeutic Therapeutic Effect Variant WNT Signaling Pathway base desensitization effective therapy mRNA Stability migration nerve stem cell nervous system development notch protein novel therapeutics numb protein prevent receptor self-renewal stem cell self renewal stem cells stem-like cell stemness therapeutic development therapeutic target trafficking

项目摘要

PROJECT SUMMARY Glioblastoma is the most common type of brain tumor and is currently incurable. The lack of effective treatments highlights the urgent need for identifying mechanism-based therapeutic approaches. Substantial experimental evidence has recently revealed a population of neural stem cell (NSC)-like glioma stem cells (GSCs) that possess an inexhaustible ability to self-renew as the “root” of glioblastoma. Like NSCs, GSCs are known to maintain their stemness by interacting with niches, which provides proper cues to prevent them from differentiating. But how GSCs manage to sustain their self-renewal capacity in the sub-optimal environment outside the niches, particularly during the process of invasion and migration, remains less clear. As part of our effort to identify potential glioma suppressors involved in the regulation of central nervous system development, we discovered that RNA binding protein Quaking (QKI) is a major regulator of NSC and GSC self-renewal. QKI is frequently deleted or mutated in human glioblastomas. Using a newly established animal model, we genetically demonstrated that QKI is a bona fide glioma suppressor whose depletion strongly promotes gliomagenesis. Functionally, we revealed that QKI is a key regulator of cellular endocytosis that controls receptor trafficking, degradation, and signaling desensitization. Specifically, we showed that depletion of QKI led to the enrichment of cytoplasmic membrane-bound Wnt and Notch receptors (Frizzled and Notch1) and subsequent signal hyperactivation. Given that Wnt and Notch1 are two major signaling cascades involved in maintaining NSC and GSC stemness against differentiation, we propose that QKI modulates NSC and GSC self-renewal and gliomagenesis by controlling endolysosome-mediated Frizzled and Notch1 degradation. To test this hypothesis, in Aim 1, we will determine how QKI regulates the endolysosome-dependent degradation of Wnt receptor Frizzled in NSCs and GSCs. In Aim 2, we will delineate the molecular mechanism by which QKI modulates RNA alternative splicing of the endocytic regulator Numb and the endolysosomal Notch1 degradation. Together, these studies will elucidate the molecular mechanisms underlying QKI-mediated endolysosome-dependent regulation of Wnt and Notch1 signal activation, and more importantly, they will contribute to the development of therapeutic strategies that specifically target QKI-depleted glioblastoma.

项目总结