EMT Regulation by Autophagy: A New Perspective in Glioblastoma Biology

Abstract

Epithelial-to-mesenchymal transition (EMT) and its reverse process MET naturally occur during development and in tissue repair in vertebrates. EMT is also recognized as the crucial event by which cancer cells acquire an invasive phenotype through the activation of specific transcription factors and signalling pathways. Even though glial cells have a mesenchymal phenotype, an EMT-like process tends to exacerbate it during gliomagenesis and progression to more aggressive stages of the disease. Autophagy is an evolutionary conserved degradative process that cells use in order to maintain a proper homeostasis, and defects in autophagy have been associated to several pathologies including cancer. Besides modulating cell resistance or sensitivity to therapy, autophagy also affects the migration and invasion capabilities of tumor cells. Despite this evidence, few papers are present in literature about the involvement of autophagy in EMT-like processes in glioblastoma (GBM) so far. This review summarizes the current understanding of the interplay between autophagy and EMT in cancer, with special regard to GBM model. As the invasive behaviour is a hallmark of GBM aggressiveness, defining a new link between autophagy and EMT can open a novel scenario for targeting these processes in future therapeutical approaches.

Keywords: Wnt/β-catenin signalling; autophagy; cadherins; epithelial-to-mesenchymal transition (EMT); glioblastoma (GBM).

Figure 1

Effects of autophagy modulation on GBM migration/invasion capabilities from opposite point of views. (A) Autophagy induction promotes GBM cells invasiveness and viceversa. Upon different stimuli, autophagy is activated and a more invasive phenotype is observed in some models of GBM cells (right). Conversely, when autophagy is impaired by genetic knockdown of some autophagy-related genes, a less invasive phenotype is obtained (left). TGFβ, Tumor necrosis factor β; TMZ, Temozolomide. (B) Autophagy modulation promotes EMT/MET-like shifts in GBM cells. In nutrient-rich conditions, hyperactivation of the mTORC1/2 complexes impairs autophagy and Wnt pathway is active thus allowing β-catenin translocation to the nucleus where it promotes the transcription of pro-invasive molecules. In this condition, EMT players of the SNAI family express and repress cadherins expression. The genetic knockdown of autophagy related genes exacerbates the mesenchymal phenotype and enhances the cell migration capability. Upon autophagy induction, shown on the right, Dishvelled (DVL) is degraded and Wnt pathway inactivated leading to β-catenin accumulation into the cytosol. In autophagic cells, SNAI factors are down-regulated and, consequently, N-cadherin accumulates and binds β-catenin, thus promoting cell-cell adhesion.

Figure 1

Effects of autophagy modulation on GBM migration/invasion capabilities from opposite point of views. (A) Autophagy induction promotes GBM cells invasiveness and viceversa. Upon different stimuli, autophagy is activated and a more invasive phenotype is observed in some models of GBM cells (right). Conversely, when autophagy is impaired by genetic knockdown of some autophagy-related genes, a less invasive phenotype is obtained (left). TGFβ, Tumor necrosis factor β; TMZ, Temozolomide. (B) Autophagy modulation promotes EMT/MET-like shifts in GBM cells. In nutrient-rich conditions, hyperactivation of the mTORC1/2 complexes impairs autophagy and Wnt pathway is active thus allowing β-catenin translocation to the nucleus where it promotes the transcription of pro-invasive molecules. In this condition, EMT players of the SNAI family express and repress cadherins expression. The genetic knockdown of autophagy related genes exacerbates the mesenchymal phenotype and enhances the cell migration capability. Upon autophagy induction, shown on the right, Dishvelled (DVL) is degraded and Wnt pathway inactivated leading to β-catenin accumulation into the cytosol. In autophagic cells, SNAI factors are down-regulated and, consequently, N-cadherin accumulates and binds β-catenin, thus promoting cell-cell adhesion.

Figure 2

Targeting autophagy in GBM therapy. The effects of different therapeutic combinations on autophagy and the outcome on GBM progression in patients are shown. Chloroquine or hydroxy-chloroquine (CQ/HCQ) addition to standard protocols (TMZ/IR, temozolomide/radiation therapy) impairs the autophagy flux and sensitizes GBM to the treatment (pink box). Otherwise, several chemical compounds and mTOR inhibitors, that are able to stimulate autophagy, also increase the efficacy of the standard treatments (green boxes). THC, tetrahydrocannabinol.