Abstract

Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1High;CHD7Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1High;CHD7Low xenograft model.

BMI1 and CHD7 are chromatin remodelling genes with a role in medulloblastoma pathogenesis. Here, the authors demonstrate that the BMI1High/CHD7Low signature mediates metabolic adaptation in G4 MB and predicts response to inositol treatment either alone or in combination with chemotherapy.

Details

Title
Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation
Author
Badodi Sara 1   VIAFID ORCID Logo  ; Pomella Nicola 1 ; Zhang, Xinyu 1 ; Rosser, Gabriel 1   VIAFID ORCID Logo  ; Whittingham, John 2 ; Victoria, Niklison-Chirou Maria 3   VIAFID ORCID Logo  ; Lim, Yau Mun 4   VIAFID ORCID Logo  ; Brandner, Sebastian 4   VIAFID ORCID Logo  ; Morrison, Gillian 5 ; Pollard, Steven M 5   VIAFID ORCID Logo  ; Bennett, Christopher D 6 ; Clifford, Steven C 7 ; Peet, Andrew 6 ; Albert, Basson M 8   VIAFID ORCID Logo  ; Marino, Silvia 1   VIAFID ORCID Logo 

1  Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133) 
2  Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
3  Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133); University of Bath, Centre for Therapeutic Innovation (CTI-Bath), Department of Pharmacy & Pharmacology, Bath, UK (GRID:grid.7340.0) (ISNI:0000 0001 2162 1699) 
4  UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK (GRID:grid.52996.31) (ISNI:0000 0000 8937 2257) 
5  The University of Edinburgh, Centre for Regenerative Medicine & Cancer Research UK Edinburgh Centre, Edinburgh, UK (GRID:grid.4305.2) (ISNI:0000 0004 1936 7988) 
6  Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK (GRID:grid.6572.6) (ISNI:0000 0004 1936 7486); Birmingham Women and Children’s Hospital, Birmingham, UK (GRID:grid.415246.0) (ISNI:0000 0004 0399 7272) 
7  Newcastle University Centre for Cancer, Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle upon Tyne, UK (GRID:grid.1006.7) (ISNI:0000 0001 0462 7212) 
8  Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764); MRC Centre for Neurodevelopmental Disorders, King’s College London, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-22379-7
ProQuest document ID
2511567161
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.