Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation

Sara Badodi; Nicola Pomella; Xinyu Zhang; Gabriel Rosser; John Whittingham; Maria Victoria Niklison-Chirou; Yau Mun Lim; Sebastian Brandner; Gillian Morrison; Steven M Pollard; Christopher D Bennett; Steven C Clifford; Andrew Peet; M Albert Basson; Silvia Marino

doi:10.1038/s41467-021-22379-7

Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation

Nat Commun. 2021 Apr 12;12(1):2148. doi: 10.1038/s41467-021-22379-7.

Authors

Sara Badodi¹, Nicola Pomella¹, Xinyu Zhang¹, Gabriel Rosser¹, John Whittingham², Maria Victoria Niklison-Chirou^{1

3}, Yau Mun Lim⁴, Sebastian Brandner⁴, Gillian Morrison⁵, Steven M Pollard⁵, Christopher D Bennett^{6

7}, Steven C Clifford⁸, Andrew Peet^{6

7}, M Albert Basson^{2

9}, Silvia Marino¹⁰

Affiliations

¹ Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
² Centre for Craniofacial and Regenerative Biology, King's College London, London, UK.
³ Centre for Therapeutic Innovation (CTI-Bath), Department of Pharmacy & Pharmacology, University of Bath, Bath, UK.
⁴ UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK.
⁵ Centre for Regenerative Medicine & Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK.
⁶ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁷ Birmingham Women and Children's Hospital, Birmingham, UK.
⁸ Newcastle University Centre for Cancer, Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle upon Tyne, UK.
⁹ MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK.
¹⁰ Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK. [email protected].

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 BMI1^High;CHD7^Low 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 BMI1^High;CHD7^Low xenograft model.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptation, Physiological* / drug effects
Animals
Cell Count
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Cerebellar Neoplasms / genetics*
Cisplatin / pharmacology
DNA-Binding Proteins / metabolism
Drug Synergism
Epigenesis, Genetic* / drug effects
Humans
Inositol / pharmacology*
Medulloblastoma / genetics*
Mice
Neural Stem Cells / metabolism
Oxygen Consumption / drug effects
Phosphatidylinositols / metabolism
Polycomb Repressive Complex 1 / metabolism
Promoter Regions, Genetic / genetics
Proto-Oncogene Proteins / metabolism
Signal Transduction
T-Box Domain Proteins
TOR Serine-Threonine Kinases / metabolism
Xenograft Model Antitumor Assays

Substances

Bmi1 protein, mouse
Chd7 protein, mouse
DNA-Binding Proteins
Eomes protein, mouse
Phosphatidylinositols
Proto-Oncogene Proteins
T-Box Domain Proteins
Inositol
Polycomb Repressive Complex 1
TOR Serine-Threonine Kinases
Cisplatin

Abstract

Publication types

MeSH terms

Substances

Grants and funding