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

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $405,105

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10910020
- **Project number:** 5R01NS132944-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jian Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $405,105
- **Award type:** 5
- **Project period:** 2023-08-21 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10910020

## Citation

> US National Institutes of Health, RePORTER application 10910020, The role of membrane homoeostasis of neural stem cell and glioma stem cells in neural development and gliomagenesis (5R01NS132944-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10910020. Licensed CC0.

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