Fig. 3.

Molecular mechanisms regulating EMT-like programs in GSCs. Several interconnected signaling pathways have been shown to activate EMT-like processes in GBM, promoting the acquisition of a mesenchymal phenotype in GSCs. Signaling pathways whose deregulation/aberrant activity has been found to promote the expression of EMT-associated genes in GBM primarily include the Wnt/β-catenin, hepatocyte growth factor (HGF)/c-MET, and TGF-β pathways. Canonical Wnt/β-catenin pathway: in the absence of canonical Wnt signals, GSK3β readily phosphorylates cytoplasmic β-catenin, targeting it for subsequent degradation through the ubiquitin–proteasome pathway. However, when Wnt ligands bind to a Frizzled receptor, GSK3β activity is inhibited (although this inhibition can also be mediated through the PI3K/AKT pathway). Active Wnt signaling thereby allows β-catenin to accumulate in the cytoplasm, which can subsequently translocate into the nucleus and bind to LEF/TCF transcription factors, in doing so activating the expression of target EMT genes. HGF/c-MET pathway: the c-MET receptor tyrosine kinase is often aberrantly overexpressed in GBM cells, including glioma stem-like cells, and has been implicated in enhancing tumor invasiveness by modulating the expression of genes involved in EMT. Upon binding its cognate ligand, HGF, c-MET can activate the RAS/MAPK and PI3K/AKT signaling cascades, both of which have been shown to lead to increased expression of transcription factors involved in glioma cell motility and invasion. TGF-β pathway: binding of TGF-β1 or TGF-β2 to either type I/II TGF-β receptors induces phosphorylation, and thereby activation, of receptor-regulated SMAD proteins (SMAD2/3). Activated SMAD2/3 is then able to interact with the common-mediator SMAD4, forming a trimeric SMAD complex that is free to translocate into the nucleus and cooperate with transcription factors to induce the expression of EMT-related genes. Moreover, TGF-β signaling can also induce EMT through SMAD-independent pathways through activation of the MAPK and PI3K/AKT signaling cascades, but these mechanisms have not been studied extensively in the context of GBM invasion