Oncogenic dependence of glioma cells on kish/TMEM167A regulation of vesicular trafficking

• Published in: Glia 2019-02, Vol.67 (2), p.404-417
• Main Authors: Portela, Marta, Segura‐Collar, Berta, Argudo, Irene, Sáiz, Almudena, Gargini, Ricardo, Sánchez‐Gómez, Pilar, Casas‐Tintó, Sergio
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Animals; Animals, Genetically Modified; Brain - cytology; Brain cancer; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brefeldin A; Cell Line, Tumor; Dependence; Disease Models, Animal; Drosophila melanogaster; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; EGFR; Endosomes; Enzyme Inhibitors - pharmacology; Epidermal growth factor receptors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Female; Fruit flies; Gene expression; Gene Expression Regulation, Neoplastic - physiology; Genetic screening; glia; Glioblastoma; Glioma; Glioma - metabolism; Glioma - pathology; Glioma cells; Golgi apparatus; Heterografts; Humans; kish/TMEM167A; Lesions; Leupeptins - pharmacology; Localization; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Lysosomes; Male; Malignancy; Mice; Modulators; proteasome; Proteasomes; Protein Transport - genetics; Protein turnover; RNA Interference - physiology; RNA-mediated interference; Toxicity; vesicular trafficking
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23551

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. Kish and its human orthologue TMEM167A regulate vesicular trafficking. GB cells displace vesicle trafficking towards EGFR recycling via kish/TMEM167A. Kish/TMEM167A downregulation induces EGFR proteasomal degradation that prevents GB progression.