Imatinib and Nilotinib increase glioblastoma cell invasion via Abl-independent stimulation of p130Cas and FAK signalling

Abstract

Imatinib was the first targeted tyrosine kinase inhibitor to be approved for clinical use, and remains first-line therapy for Philadelphia chromosome (Ph+)-positive chronic myelogenous leukaemia. We show that treatment of human glioblastoma multiforme (GBM) tumour cells with imatinib and the closely-related drug, nilotinib, strikingly increases tyrosine phosphorylation of p130Cas, focal adhesion kinase (FAK) and the downstream adaptor protein paxillin (PXN), resulting in enhanced cell migration and invasion. Imatinib and nilotinib-induced tyrosine phosphorylation was dependent on expression of p130Cas and FAK activity and was independent of known imatinib targets including Abl, platelet derived growth factor receptor beta (PDGFRβ) and the collagen receptor DDR1. Imatinib and nilotinib treatment increased two dimensional cell migration and three dimensional radial spheroid invasion in collagen. In addition, silencing of p130Cas and inhibition of FAK activity both strongly reduced imatinib and nilotinib stimulated invasion. Importantly, imatinib and nilotinib increased tyrosine phosphorylation of p130Cas, FAK, PXN and radial spheroid invasion in stem cell lines isolated from human glioma biopsies. These findings identify a novel mechanism of action in GBM cells for two well established front line therapies for cancer resulting in enhanced tumour cell motility.

Recapitulating in vivo-like plasticity of glioma cell invasion along blood vessels and in astrocyte-rich stroma

“…In unperturbed brain, fibrillar collagens are expressed mainly along blood vessels but not in the parenchyma (Bellail et al 2004 ; Gritsenko et al 2012 ), and upregulated in a subset of clinical gliomas in the tumor mass and perivascular regions (Huijbers et al 2010 ; Payne and Huang 2013 ; Motegi et al 2014 ). Type I collagen scaffolds are effectively invaded by glioma cells (Kaufman et al 2005 ; Yang et al 2010 ; Frolov et al 2016 ); however, the relevance of collagen as substrate for diffuse glioma cell infiltration beyond the tumor core remains unclear (Rape et al 2014 ). rBM and cross-linked hyaluronan both represent key components of the brain stroma and, like synthetic hydrogels, provide soft environments similar to brain tissue; however, they lack other adhesion ligands and cell-derived brain structures, such as astrocyte networks and myelinated axons (Gritsenko et al 2012 ).…”

A Short Region of Connexin43 Reduces Human Glioma Stem Cell Migration, Invasion, and Survival through Src, PTEN, and FAK

“…Not surprisingly, both Src –/– and FAK ( Ptk2 )−/− fibroblasts display impaired migration ( Ilić et al., 1995 , Klinghoffer et al., 1999 ). c-Src and FAK are required for the processes of cell invasion and migration in tumor cells ( Carragher et al., 2006 , van Nimwegen et al., 2005 ), including glioblastoma ( Du et al., 2009 , Lindemann et al., 2011 ) and GSCs ( Frolov et al., 2016 , Liu et al., 2016 ). In fact, the activity of both c-Src and FAK are augmented in glioblastomas ( Riemenschneider et al., 2005 , Zhang et al., 2011 ).…”

Adaptive adhesion systems mediate glioma cell invasion in complex environments

“…In addition to rBM, other diverse 2D and 3D in vitro assays have been developed to model glioma cell invasion into brain stroma (Rao et al, 2014;Rape et al, 2014). 3D collagen scaffolds, broadly used in cancer research, are effectively invaded by glioma cells (Frolov et al, 2016;Kaufman et al, 2005); furthermore, combined targeting of β1 integrin and JNK kinase significantly inhibited glioma cell invasion in type I collagen gels (Vehlow et al, 2017). However, the relevance of fibrillar collagen for the largely collagenfree brain parenchyma remains unclear (Gritsenko et al, 2012;Rape et al, 2014).…”