title: Inference of Low and High-Grade Glioma Gene Regulatory Networks Delineates the Role of Rnd3 in Establishing Multiple Hallmarks of Cancer.
abstract: Gliomas are a highly heterogeneous group of brain tumours that are refractory to treatment, highly invasive and pro-angiogenic. Glioblastoma patients have an average survival time of less than 15 months. Understanding the molecular basis of different grades of glioma, from well differentiated, low-grade tumours to high-grade tumours, is a key step in defining new therapeutic targets. Here we use a data-driven approach to learn the structure of gene regulatory networks from observational data and use the resulting models to formulate hypothesis on the molecular determinants of glioma stage. Remarkably, integration of available knowledge with functional genomics datasets representing clinical and pre-clinical studies reveals important properties within the regulatory circuits controlling low and high-grade glioma. Our analyses first show that low and high-grade gliomas are characterised by a switch in activity of two subsets of Rho GTPases. The first one is involved in maintaining normal glial cell function, while the second is linked to the establishment of multiple hallmarks of cancer. Next, the development and application of a novel data integration methodology reveals novel functions of RND3 in controlling glioma cell migration, invasion, proliferation, angiogenesis and clinical outcome.
authors.affiliation: Centre for Computational Biology and Modelling (CCBM), Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom; INSERM U1029, University Bordeaux, Pessac, France.
authors.forename: Kim
authors.initials: K
authors.lastname: Clarke
authors.affiliation: INSERM U1029, University Bordeaux, Pessac, France; NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Thomas
authors.initials: T
authors.lastname: Daubon
authors.affiliation: Medical School, University of Birmingham, Birmingham, United Kingdom; School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Nil
authors.initials: N
authors.lastname: Turan
authors.affiliation: INSERM U1029, University Bordeaux, Pessac, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Soulet
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Maihafizah
authors.initials: M
authors.lastname: Mohd Zahari
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Katie R
authors.initials: KR
authors.lastname: Ryan
authors.affiliation: Medical School, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Sarah
authors.initials: S
authors.lastname: Durant
authors.affiliation: Computer Science, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Shan
authors.initials: S
authors.lastname: He
authors.affiliation: Centre for Computational Biology and Modelling (CCBM), Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Herbert
authors.affiliation: Centre for Computational Biology and Modelling (CCBM), Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Ankers
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: John K
authors.initials: JK
authors.lastname: Heath
authors.affiliation: NorLux Neuro-Oncology, Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.affiliation: Medical School, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Roy
authors.initials: R
authors.lastname: Bicknell
authors.affiliation: School of Biosciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Hotchin
authors.affiliation: INSERM U1029, University Bordeaux, Pessac, France.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bikfalvi
authors.affiliation: Centre for Computational Biology and Modelling (CCBM), Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Falciani
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D056915:DNA Copy Number Variations; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics*; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering; D020741:rho GTP-Binding Proteins / Q000235:genetics*
chemical_list: D034741:RNA, Small Interfering; C508705:RND3 protein, human; D020741:rho GTP-Binding Proteins