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

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.
The authors would like to acknowledge Alberto Ferrús, Paco Martín,María Losada, and Elena Santana for critical comments on the manu-script. MP holds a fellowship from the Juan de la Cierva program IJCI-2014-19272 and SCT holds a contract from the Ramón y Cajal pro-gram RYC 2012-11410 from the Spanish MICINN. R.G. has beenfunded by the AECC Scientific Foundation. Research has been fundedby grants from the Ministerio de Economía y Competitividad(MINECO-RETOS) SAF2015-65175-R to PSG and (MINECO-EXCE-LENCIA) BFU2015-65685P to SCT.