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

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

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20 Citations (SciVal)

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.
Original languageEnglish
Article number2148
Number of pages16
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 12 Apr 2021

Bibliographical note

Funding Information:
We are grateful to the BSU staff for help in the daily care of our mouse colony and to the Blizard Core Facilities (Imaging and FACS) for technical advice. Access to medulloblastoma tissue was obtained through the CCLG tissue bank (project number 2015 BS 05). This work is supported by grants of the Medical Research Council UK (MR/ N000528/1) to S.M. and M.A.B. and a Brain Tumour Research Centre of Excellence award to S.M. Y.M.L. is funded by a Cancer Research UK Accelerator grant Cl 15121A 20256. Funding from Children with Cancer UK (15/188), Action Medical Research and The Brain Tumour Charity (GN2181) to C.D.B., S.C.C. and A.P. are also acknowledged. A.P. was funded by an NIHR Research Professorship (NIHR-RP-R2-12-019). S.Br. is partly supported by the Department of Health’s NIHR Biomedical Research Centre’s funding scheme to University College London Hospitals.

Data availability
The authors declare that all the data supporting the findings of this study are available
within the article and its Supplementary Information files. The datasets generated in this
study and processed data are available in the NCBI Gene Expression Omnibus database
(GSE156077) or are available from the corresponding author upon reasonable request.
Publicly available datasets used in the study: GSE85217 (Expression data from primary
medulloblastoma samples), Reactome (https://reactome.org/), Panther Gene Ontology
tool (http://geneontology.org/), Swiss-Prot (https://www.uniprot.org/statistics/SwissProt), PhosphoSite (https://www.phosphosite.org/), Phospho.ELM (http://phospho.elm.
eu.org/) and PhosphoPOINT (http://kinase.bioinformatics.tw/). Source data are provided
with this paper.

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