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

Abstract

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 EGFR-TMEM167A-p53 Axis Defines the Aggressiveness of Gliomas

“…We observed an increase in the survival of the mice that had been injected with shTMEM167A cells in comparison with the control-injected mice ( Figure 5A). Moreover, TMEM167A knock-down (KD) induced a decrease in the amount of Phospho-AKT ( Figure 5B), confirming our previous results [10] and demonstrating an efficient inhibition of EGFR signaling after the in vivo downregulation of TMEM167A. Even though this established cell line overexpresses EGFR, U87 cells do not carry alterations in this gene.…”

“…Recently, we have shown that the downregulation of TMEM167A or its fly orthologue, Kish, diminish glioma growth by affecting the endo-lysosomal system. Moreover, our previous data suggested that the downregulation of TMEM167A/Kish induces degradation of EGFR [10]. However, we had not explored the relation between TMEM167A expression and/or function with the genetic status of EGFR and TP53.…”

“…Based on that, we searched for other molecules that could modulate the trafficking of membrane receptors in wild-type p53 GBMs. We focused on TMEM167A, as we had previously linked this gene to EGFR regulation in gliomas [10]. We measured a strong association between the expression of this gene and the worse survival of patients with wild-type p53 tumors.…”

Modeling invasion patterns in the glioblastoma battlefield

“…Glial cells respond to this oncogenic transformation and reproduce all main features of the disease, including glial expansion and invasion, but in a shorter period of time. This Drosophila model has been used for drug and genetic screenings and the results have been validated in human GB cells (REFs) (12)(13)(14).Agents involved in the battlefield GB growth and migration are driven by specific signaling pathways as well as interactions between the tumor and its extracellular microenvironment. In our study, we include the cell membrane protrusions (TMs) as driving factors of tumor progression, as well as cell response to signaling gradients and the interplay with the Extra Cellular Matrix (ECM).…”

“…Glial cells respond to this oncogenic transformation and reproduce all main features of the disease, including glial expansion and invasion, but in a shorter period of time. This Drosophila model has been used for drug and genetic screenings and the results have been validated in human GB cells (REFs) (12)(13)(14).…”