Hg-99a Patient-derived Paediatric High Grade Glioma and Dipg Cell Culture Panel Recapitulating the Genotypic and Phenotypic Diversity of the Disease
Year: 2016
Type: article
Abstract: Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) continue to have a dismal prognosis due to their aggressive and infiltrative nature coupled with a lack of well-characterised preclinical models. We have collected and/or established 26 primary patient-derived models of pHGG and DIPG, cultured under stem cell conditions either in 2D (adherent on laminin) or 3D (neurospheres), and characterised extensively by means of exome/RNA sequencing, 450K methylation, immunophenotyping, in vitro clonogenicity, invasion and migration properties, drug sensitivity and in vivo tumorigenicity. The panel comprises 15 non-brainstem pHGG (n = 13 from cerebral hemispheres; n = 2 from thalamus) and 13 DIPG. They include H3.3G34R, H3.3K27M and H3.1K27M subtypes (with co-segregating ATRX, FGFR1, PPM1D and ACVR1 mutations) as well as histone wild-type samples including PDGFRA and NF1 mutations and an ETV6:NTRK3 fusion. The heterogeneous stem cell (Nestin, Sox2, Musashi-1) and differentiation (GFAP, Olig2, CNPase, TUJ-1) marker expression profile of the primary tumour is maintained in both 2D and 3D culture, as well as the orthotopic xenograft where assessed. We observed at least four patterns of invasion into matrigel (none, single cell, collective, expansive) and a differential capacity for migration onto different matrices (matrigel, fibronectin, tenascin-C), with certain cells appearing to rely on a preferential motility mechanism based on adhesion molecules (e.g. integrins) rather than proteases (e.g. MMPs). High-throughput chemotherapeutic and small molecule screens are aimed at uncovering genetic and phenotypic dependencies across the diverse make-up of pGBM and DIPG, which may be rapidly assessed in vivo and translated to appropriately designed clinical trials.
Source: Neuro-Oncology
Authors: Mara Vinci, Valeria Molinari, Kathryn Taylor, Diana Carvalho, Anna Burford, Alan Mackay, Sergey Popov, Mariama Fofama, Janat Fazal-Salom, Lynn Bjerke, Jessica K.R. Boult, Helen Pemberton, Christopher J. Lord, Louise Howell, Jane Pears, Angela Mastronuzzi, Andrea Carai, Lynley V. Marshall, Stergios Zacharoulis, Sucheta Vaidya, Henry C. Mandeville, Leslie R. Bridges, Andrew J. Martin, Safa Al-Sarraj, Christopher Chandler, Simon P. Robinson, Nagore G. Olaciregui, Mariona Sunol, Jaume Mora, Carmen de Torres, Ofelia Cruz, Michelle Monje, Andrew S. Moore, Angel M. Carcaboso, Chris Jones
Institutions: Institute of Cancer Research, University Hospital of Wales, Children's Health Ireland at Crumlin, Bambino Gesù Children's Hospital, Istituti di Ricovero e Cura a Carattere Scientifico, Royal Marsden Hospital, St George's Hospital, King's College Hospital, Hospital Sant Joan de Déu Barcelona, Stanford University, Queensland Children’s Medical Research Institute
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2435145738