Lineage specification in glioblastoma is regulated by METTL7B
Myrianni Constantinou,
James Nicholson,
Xinyu Zhang,
Eleni Maniati,
Sara Lucchini,
Gabriel Rosser,
Claire Vinel,
Jun Wang,
Yau Mun Lim,
Sebastian Brandner,
Sven Nelander,
Sara Badodi,
Silvia Marino
Affiliations
Myrianni Constantinou
Brain Tumour Research Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK
James Nicholson
Brain Tumour Research Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK
Xinyu Zhang
Brain Tumour Research Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK
Eleni Maniati
Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6AS, UK
Sara Lucchini
Brain Tumour Research Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK
Gabriel Rosser
Brain Tumour Research Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK
Claire Vinel
Brain Tumour Research Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK
Jun Wang
Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6AS, UK
Yau Mun Lim
Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, and Department of Neurodegenerative Disease, Queen Square, Institute of Neurology, University College London, Queen Square, London, UK
Sebastian Brandner
Division of Neuropathology, The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, and Department of Neurodegenerative Disease, Queen Square, Institute of Neurology, University College London, Queen Square, London, UK
Sven Nelander
Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden
Sara Badodi
Brain Tumour Research Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK
Silvia Marino
Brain Tumour Research Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University London, London, UK; Corresponding author
Summary: Glioblastomas are the most common malignant brain tumors in adults; they are highly aggressive and heterogeneous and show a high degree of plasticity. Here, we show that methyltransferase-like 7B (METTL7B) is an essential regulator of lineage specification in glioblastoma, with an impact on both tumor size and invasiveness. Single-cell transcriptomic analysis of these tumors and of cerebral organoids derived from expanded potential stem cells overexpressing METTL7B reveal a regulatory role for the gene in the neural stem cell-to-astrocyte differentiation trajectory. Mechanistically, METTL7B downregulates the expression of key neuronal differentiation players, including SALL2, via post-translational modifications of histone marks.
