Inactivation of the ATMIN/ATM pathway protects against glioblastoma formation
Sophia M Blake,
Stefan H Stricker,
Hanna Halavach,
Anna R Poetsch,
George Cresswell,
Gavin Kelly,
Nnennaya Kanu,
Silvia Marino,
Nicholas M Luscombe,
Steven M Pollard,
Axel Behrens
Affiliations
Sophia M Blake
Adult Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom; Lincoln's Inn Fields Laboratory, The Francis Crick Institute, London, United Kingdom
Stefan H Stricker
Samantha Dickson Brain Cancer Unit and Department of Cancer Biology, UCL Cancer Institute, University College London, London, United Kingdom
Hanna Halavach
Adult Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom; Lincoln's Inn Fields Laboratory, The Francis Crick Institute, London, United Kingdom
Anna R Poetsch
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
George Cresswell
Lincoln's Inn Fields Laboratory, The Francis Crick Institute, London, United Kingdom; Bioinformatics and Computational Biology Laboratory, The Francis Crick Institute, London, United Kingdom
Gavin Kelly
Lincoln's Inn Fields Laboratory, The Francis Crick Institute, London, United Kingdom; Bioinformatics and Biostatistics, The Francis Crick Institute, London, United Kingdom
Nnennaya Kanu
Adult Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom; Lincoln's Inn Fields Laboratory, The Francis Crick Institute, London, United Kingdom
Silvia Marino
Blizard Institute, Barts and the London School of Medicine and Dentistry, London, United Kingdom
Nicholas M Luscombe
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
Steven M Pollard
Samantha Dickson Brain Cancer Unit and Department of Cancer Biology, UCL Cancer Institute, University College London, London, United Kingdom
Axel Behrens
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
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.
