title: Coordination of signalling networks and tumorigenic properties by ABL in glioblastoma cells.
abstract: The 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 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 highlighted by down-regulation of epithelial markers and up-regulation of mesenchymal markers. Cells with permanent ABL inhibition exhibit enhanced motility and invasive capabilities, while proliferation and tumorigenic properties are 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 coincide 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.
authors.affiliation: Aix-Marseille Université, CNRS, Developmental Biology Institute of Marseille (IBDM), Parc Scientifique de Luminy, Marseille, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lamballe
authors.affiliation: Aix-Marseille Université, CNRS, Developmental Biology Institute of Marseille (IBDM), Parc Scientifique de Luminy, Marseille, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Toscano
authors.affiliation: Aix-Marseille Université, CNRS, Developmental Biology Institute of Marseille (IBDM), Parc Scientifique de Luminy, Marseille, France.
authors.forename: Filippo
authors.initials: F
authors.lastname: Conti
authors.affiliation: Aix-Marseille Université, CNRS, Developmental Biology Institute of Marseille (IBDM), Parc Scientifique de Luminy, Marseille, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Arechederra
authors.affiliation: Aix-Marseille Université, Inserm, CRO2 UMR S911, Marseille, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Baeza
authors.affiliation: Aix-Marseille Université, Inserm, CRO2 UMR S911, Marseille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Figarella-Branger
authors.affiliation: Aix-Marseille Université, CNRS, Developmental Biology Institute of Marseille (IBDM), Parc Scientifique de Luminy, Marseille, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Helmbacher
authors.affiliation: Aix-Marseille Université, CNRS, Developmental Biology Institute of Marseille (IBDM), Parc Scientifique de Luminy, Marseille, France.
authors.forename: Flavio
authors.initials: F
authors.lastname: Maina
mesh_terms: D015415:Biomarkers; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D000066673:Cell Self Renewal / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D016315:Proto-Oncogene Proteins c-abl
keywords: ABL; RTK signalling; glioblastomas; migration and invasion; tumorigenicity and self-renewal