An Adult Drosophila Glioma Model for Studying Pathometabolic Pathways of Gliomagenesis

Abstract

Glioblastoma multiforme (GBM), the most prevalent brain tumor in adults, has extremely poor prognosis. Frequent genetic alterations that activate epidermal growth factor receptor (EGFR) and phosphatidylinositol-3 kinase (PI3K) signaling, as well as metabolic remodeling, have been associated with gliomagenesis. To establish a whole-animal approach that can be used to readily identify individual pathometabolic signaling factors, we induced glioma formation in the adult Drosophila brain by activating the EGFR-PI3K pathway. Glioma-induced animals showed significantly enlarged brain volume, early locomotor abnormalities, memory deficits, and a shorter lifespan. Combining bioinformatics analysis and glial-specific gene knockdown in the adult fly glioma model, we identified four evolutionarily conserved metabolic genes, including ALDOA, ACAT1, ELOVL6, and LOX, that were involved in gliomagenesis. Silencing of ACAT1, which controls cholesterol homeostasis, reduced brain enlargement and increased the lifespan of the glioma-bearing flies. In GBM patients, ACAT1 is overexpressed and correlates with poor survival outcomes. Moreover, pharmacological inhibition of ACAT1 in human glioma cell lines revealed that it is essential for tumor proliferation. Collectively, these results imply that ACAT1 is a potential therapeutic target, and cholesterol homeostasis is strongly related to glioma formation. This in vivo model provides several rapid and robust phenotypic readouts, allowing determination of the pathometabolic pathways involved in gliomagenesis, as well as providing valuable information for novel therapeutic strategies.

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Acknowledgments

We thank Henry Sun for providing critical reagents; Yi-Hsin Pan for performing flow cytometric assays, FlyCore in Taiwan for providing reagents, and Instrument Center of National Defense Medical Center for confocal imaging facility.

Funding

This study was supported by grants from Health and Welfare surcharge of tobacco to the Ministry of Health and Welfare (MOHW106-TDU-B-211-144001 to D.-Y.H.), Ministry of Science and Technology (MOST-104-2745-B-007-002 and MOST-106-2314-B-016-012-MY3 to D.-Y.H.; MOST-105-2628-B-001-011-MY3 to T.-Y.L.; MOST-107-3017-F-007-004), Tri-Service General Hospital (TSGH-C106-004-006-008-S04 to D.-Y.H.), and Ministry of National Defense-Medical Affairs Bureau (MAB-106-019 to D.-Y.H. and MAB-106-121 to T.-Y.L.), Taipei, Taiwan, R.O.C.

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Correspondence to Tzu-Yang Lin or Dueng-Yuan Hueng.

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Chi, KC., Tsai, WC., Wu, CL. et al. An Adult Drosophila Glioma Model for Studying Pathometabolic Pathways of Gliomagenesis. Mol Neurobiol 56, 4589–4599 (2019). https://doi.org/10.1007/s12035-018-1392-2

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Keywords

  • Glioma
  • Metabolism
  • Drosophila
  • ACAT1