title: Cell migration in paediatric glioma; characterisation and potential therapeutic targeting.
abstract: BACKGROUND
  Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are highly aggressive brain tumours. Their invasive phenotype contributes to their limited therapeutic response, and novel treatments that block brain tumour invasion are needed.
  
  
  METHODS
  Here, we examine the migratory characteristics and treatment effect of small molecule glycogen synthase kinase-3 inhibitors, lithium chloride (LiCl) and the indirubin derivative 6-bromoindirubin-oxime (BIO), previously shown to inhibit the migration of adult glioma cells, on two pHGG cell lines (SF188 and KNS42) and one patient-derived DIPG line (HSJD-DIPG-007) using 2D (transwell membrane, immunofluorescence, live cell imaging) and 3D (migration on nanofibre plates and spheroid invasion in collagen) assays.
  
  
  RESULTS
  All lines were migratory, but there were differences in morphology and migration rates. Both LiCl and BIO reduced migration and instigated cytoskeletal rearrangement of stress fibres and focal adhesions when viewed by immunofluorescence. In the presence of drugs, loss of polarity and differences in cellular movement were observed by live cell imaging.
  
  
  CONCLUSIONS
  Ours is the first study to demonstrate that it is possible to pharmacologically target migration of paediatric glioma in vitro using LiCl and BIO, and we conclude that these agents and their derivatives warrant further preclinical investigation as potential anti-migratory therapeutics for these devastating tumours.
authors: 1] Leeds Institute of Cancer Studies and Pathology, University of Leeds, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK [2] Yorkshire Regional Centre for Paediatric Oncology and Haematology, Leeds General Infirmary, Great George Street, Leeds, LS1 3EX, UK.
authors: J V
authors: JV
authors: Cockle
authors: Yorkshire Regional Centre for Paediatric Oncology and Haematology, Leeds General Infirmary, Great George Street, Leeds, LS1 3EX, UK.
authors: S
authors: S
authors: Picton
authors: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK.
authors: J
authors: J
authors: Levesley
authors: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK.
authors: E
authors: E
authors: Ilett
authors: Preclinical Therapeutics and Drug Delivery Research Program, Department of Oncology, Hospital Sant Joan de Déu Barcelona, Preclinical Therapeutics and Drug Delivery Research Program Santa Rosa, 39-57, 4th floor 08950 Esplugues de Llobregat, Barcelona, Spain.
authors: A M
authors: AM
authors: Carcaboso
authors: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK.
authors: S
authors: S
authors: Short
authors: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK.
authors: L P
authors: LP
authors: Steel
authors: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK.
authors: A
authors: A
authors: Melcher
authors: Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, 4 Blackfan Circle, HIM 930A, Boston, MA, 02115, USA.
authors: S E
authors: SE
authors: Lawler
authors: Leeds Institute of Cancer Studies and Pathology, University of Leeds, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, LS9 7TF, UK.
authors: A
authors: A
authors: Brüning-Richardson
mesh_terms: D001932:Brain Neoplasms / Q000473:pathology* / Q000628:therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002648:Child; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005910:Glioma / Q000473:pathology* / Q000628:therapy*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D010091:Oximes / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology / Q000502:physiology
chemical_list: C483321:6-bromoindirubin-3'-oxime; D007211:Indoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride
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