Journal
GLIA
Volume 67, Issue 2, Pages 404-417Publisher
WILEY
DOI: 10.1002/glia.23551
Keywords
EGFR; glia; glioma; kish/TMEM167A; lysosomes; proteasome; vesicular trafficking
Categories
Funding
- Fundacion Cientifica Asociacion Espanola Contra el Cancer
- Ministerio de Ciencia e Innovacion [IJCI-2014-19272 RYC-2012-11410]
- Ministerio de Economia y Competitividad [IJCI-2014-19272, RYC-2012-11410, BFU2015-65685P, SAF2015-65175-R]
- AECC Scientific Foundation
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Genetic lesions in glioblastoma (GB) include constitutive activation of PI3K and EGFR pathways to drive cellular proliferation and tumor malignancy. An RNAi genetic screen, performed in Drosophila melanogaster to discover new modulators of GB development, identified a member of the secretory pathway: kish/TMEM167A. Downregulation of kish/TMEM167A impaired fly and human glioma formation and growth, with no effect on normal glia. Glioma cells increased the number of recycling endosomes, and reduced the number of lysosomes. In addition, EGFR vesicular localization was primed toward recycling in glioma cells. kish/TMEM167A downregulation in gliomas restored endosomal system to a physiological state and altered lysosomal function, fueling EGFR toward degradation by the proteasome. These endosomal effects mirrored the endo/lysosomal response of glioma cells to Brefeldin A (BFA), but not the Golgi disruption and the ER collapse, which are associated with the undesirable toxicity of BFA in other cancers. Our results suggest that glioma growth depends on modifications of the vesicle transport system, reliant on kish/TMEM167A. Noncanonical genes in GB could be a key for future therapeutic strategies targeting EGFR-dependent gliomas.
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