title: Inactivation of the ATMIN/ATM pathway protects against glioblastoma formation.
abstract: Glioblastoma multiforme (GBM) is the most aggressive human primary brain cancer. Using a Trp53-deficient mouse model of GBM, we show that genetic inactivation of the Atm cofactor Atmin, which is dispensable for embryonic and adult neural development, strongly suppresses GBM formation. Mechanistically, expression of several GBM-associated genes, including Pdgfra, was normalized by Atmin deletion in the Trp53-null background. Pharmacological ATM inhibition also reduced Pdgfra expression, and reduced the proliferation of Trp53-deficient primary glioma cells from murine and human tumors, while normal neural stem cells were unaffected. Analysis of GBM datasets showed that PDGFRA expression is also significantly increased in human TP53-mutant compared with TP53-wild-type tumors. Moreover, combined treatment with ATM and PDGFRA inhibitors efficiently killed TP53-mutant primary human GBM cells, but not untransformed neural stem cells. These results reveal a new requirement for ATMIN-dependent ATM signaling in TP53-deficient GBM, indicating a pro-tumorigenic role for ATM in the context of these tumors.
authors.affiliation: Adult Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom.|Lincoln's Inn Fields Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Sophia M
authors.initials: SM
authors.lastname: Blake
authors.affiliation: Samantha Dickson Brain Cancer Unit and Department of Cancer Biology, UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Stricker
authors.affiliation: Adult Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom.|Lincoln's Inn Fields Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Hanna
authors.initials: H
authors.lastname: Halavach
authors.affiliation: Lincoln's Inn Fields Laboratory, The Francis Crick Institute, London, United Kingdom.|Bioinformatics and Computational Biology Laboratory, The Francis Crick Institute, London, United Kingdom.|UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.|Okinawa Institute of Science and Technology, Okinawa, Japan.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Poetsch
authors.affiliation: Lincoln's Inn Fields Laboratory, The Francis Crick Institute, London, United Kingdom.|Bioinformatics and Computational Biology Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Cresswell
authors.affiliation: Lincoln's Inn Fields Laboratory, The Francis Crick Institute, London, United Kingdom.|Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom.
authors.forename: Gavin
authors.initials: G
authors.lastname: Kelly
authors.affiliation: Adult Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom.|Lincoln's Inn Fields Laboratory, The Francis Crick Institute, London, United Kingdom.
authors.forename: Nnennaya
authors.initials: N
authors.lastname: Kanu
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Silvia
authors.initials: S
authors.lastname: Marino
authors.affiliation: Lincoln's Inn Fields Laboratory, The Francis Crick Institute, London, United Kingdom.|Bioinformatics and Computational Biology Laboratory, The Francis Crick Institute, London, United Kingdom.|UCL Genetics Institute, Department of Genetics, Evolution and Environment, University College London, London, United Kingdom.|Okinawa Institute of Science and Technology, Okinawa, Japan.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Luscombe
authors.affiliation: Samantha Dickson Brain Cancer Unit and Department of Cancer Biology, UCL Cancer Institute, University College London, London, United Kingdom.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pollard
authors.affiliation: Adult Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom.|Lincoln's Inn Fields Laboratory, The Francis Crick Institute, London, United Kingdom.|Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
authors.forename: Axel
authors.initials: A
authors.lastname: Behrens
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D005909:Glioblastoma / Q000473:pathology* / Q000517:prevention & control; D006801:Humans; D051379:Mice; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency
chemical_list: C554480:ATMIN protein, mouse; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse
keywords: ATM; ATMIN; PDGFRa; cancer biology; glioblastoma; human; mouse; p53