Using glioblastoma (GBM) as a cellular paradigm, our studies exemplify the high vulnerability of cells to inhibition of the Tyrosine Kinase Abl. This is illustrated by loss of tumorigenic and self-renewal properties accompanied by drastic changes in the expression and/or phosphorylation levels of multiple signalling components. Such molecular and biological state can be restored through Abl signalling restoration, demonstrating the reversibility of changes in cell competence.

 

Coordination of signalling networks and tumorigenic properties by ABL in glioblastoma cells
Fabienne Lamballe1,*, Sara Toscano1,*, Filippo Conti1,*, Maria Arechederra1, Nathalie Baeza2, Dominique Figarella-Branger2, Françoise Helmbacher1 and Flavio Maina1
1 Aix-Marseille Université, CNRS, Developmental Biology Institute of Marseille (IBDM), Parc Scientifique de Luminy, Marseille, France
2 Aix-Marseille Université, Inserm, CRO2 UMR S911, Marseille, France
Oncotarget 7(46): 74747-67 (2016)
* shared first authors
Contact: Flavio Maina
flavio.maina@univ-amu.fr

 

Summary:

Maina and Helmbacher Teams publish in OncotargetThe cytoplasmic tyrosine kinase ABL exerts positive or negative effects in solid tumours according to the cellular context, thus functioning as a “switch modulator”. The therapeutic effects of drugs targeting a set of signals encompassing ABL have been explored in several types of solid tumours. However, the net contribution of ABL inhibition by these agents remains elusive as these drugs also act on other signalling components. Here, using glioblastoma (GBM) as a cellular paradigm, we report that ABL inhibition exacerbates mesenchymal features as illustrated by the down-regulation of epithelial markers and by the concomitant up-regulation of mesenchymal markers. Cells with permanent ABL inhibition exhibit enhanced motility and invasive properties, while their capacity to proliferate and form tumours is reduced. Intriguingly, permanent ABL inhibition also interferes with GBM neurosphere formation and with expression of stemness markers in sphere-cultured GBM cells. Furthermore, we show that the molecular and biological characteristics of GBM cells with impaired ABL are reversible by restoring ABL levels, thus uncovering a remarkable plasticity of GBM cells to ABL threshold. A phospho-signalling screen revealed that loss of tumorigenic and self-renewal properties in GBM cells under permanent ABL inhibition coincides with drastic changes in the expression and/or phosphorylation levels of multiple signalling components. Our findings identify ABL as a crucial player for migration, invasion, proliferation, tumorigenic, and stem-cell like properties of GBM cells. Taken together, this work supports the notion that the oncogenic role of ABL in GBM cells is associated with its capability to coordinate a signalling setting that determines tumorigenic and stem-cell like properties.