title: Mer receptor tyrosine kinase promotes invasion and survival in glioblastoma multiforme.
abstract: The infiltration of glioma cells into adjacent tissue is one of the major obstacles in the therapeutic management of malignant brain tumours, in most cases precluding complete surgical resection. Consequently, malignant glioma patients almost invariably experience tumour recurrences. Within the brain, glioma cells migrate rapidly either amoeboidly or mesenchymally to invade surrounding structures, in dependence on the extracellular environment. In addition, radiotherapy, frequently applied as adjuvant therapeutic modality, may enhance tumour cell mobility. Here, we show that the receptor tyrosine kinase Mer (MerTK) is overexpressed in glioblastoma multiforme (GBM) and that this is accompanied with increased invasive potential. MerTK expression is maintained in primary GBM-derived tumour spheres under stem cell culture conditions but diminishes significantly in serum-containing cultures with concomitant downregulation of Nestin and Sox2. Depletion of MerTK disrupts the rounded morphology of glioma cells and decreases their invasive capacity. Furthermore, the expression and phosphorylation of myosin light chain 2 are strongly associated with MerTK activity, indicating that the effect of MerTK on glioma cell invasion is mediated by actomyosin contractility. Finally, DNA damage robustly triggers the upregulation and phosphorylation of MerTK, which protects cells from apoptosis. This effect is strongly impaired upon MerTK depletion or overexpression of an inactive MerTK mutant. Collectively, our data suggests that MerTK is a novel therapeutic target in the treatment of the malignant gliomas.
authors.affiliation: Mechanisms of Cancer, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: G
authors.initials: G
authors.lastname: Moncayo
authors.forename: P
authors.initials: P
authors.lastname: Morin
authors.forename: G
authors.initials: G
authors.lastname: Xue
authors.forename: M
authors.initials: M
authors.lastname: Grzmil
authors.forename: M M
authors.initials: MM
authors.lastname: Lino
authors.forename: V
authors.initials: V
authors.lastname: Clément-Schatlo
authors.forename: S
authors.initials: S
authors.lastname: Frank
authors.forename: A
authors.initials: A
authors.lastname: Merlo
authors.forename: B A
authors.initials: BA
authors.lastname: Hemmings
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018874:Spheroids, Cellular / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics; D000076202:c-Mer Tyrosine Kinase
chemical_list: D011518:Proto-Oncogene Proteins; C097072:MERTK protein, human; D020794:Receptor Protein-Tyrosine Kinases; D000076202:c-Mer Tyrosine Kinase