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; Steven M. Pollard; Christopher D. Bennett; Steven C. Clifford; Andrew Peet; Albert Basson; Silvia Marino

doi:10.1038/s41467-021-22379-7

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, Steven M. Pollard, Christopher D. Bennett, Steven C. Clifford, Andrew Peet, Albert Basson, Silvia Marino

Department of Pharmacy & Pharmacology

Research output: Contribution to journal › Article › peer-review

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 language	English
Article number	2148
Journal	Nature Communications
Volume	12
DOIs	https://doi.org/10.1038/s41467-021-22379-7
Publication status	Published - 12 Apr 2021

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Badodi, S., Pomella, N., Zhang, X., Rosser, G., Whittingham, J., Niklison Chirou, M., Lim, Y. M., Brandner, S., Pollard, S. M., Bennett, C. D., Clifford, S. C., Peet, A., Basson, A., & Marino, S. (2021). Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation. Nature Communications, 12, [2148]. https://doi.org/10.1038/s41467-021-22379-7

Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation. / Badodi, Sara; Pomella, Nicola; Zhang, Xinyu ; Rosser, Gabriel; Whittingham, John ; Niklison Chirou, Maria; Lim, Yau Mun; Brandner, Sebastian; Pollard, Steven M.; Bennett, Christopher D.; Clifford, Steven C.; Peet, Andrew; Basson, Albert; Marino, Silvia.

In: Nature Communications, Vol. 12, 2148, 12.04.2021.

Research output: Contribution to journal › Article › peer-review

Badodi, Sara ; Pomella, Nicola ; Zhang, Xinyu ; Rosser, Gabriel ; Whittingham, John ; Niklison Chirou, Maria ; Lim, Yau Mun ; Brandner, Sebastian ; Pollard, Steven M. ; Bennett, Christopher D. ; Clifford, Steven C. ; Peet, Andrew ; Basson, Albert ; Marino, Silvia. / Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation. In: Nature Communications. 2021 ; Vol. 12.

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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.",

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AU - Zhang, Xinyu

AU - Rosser, Gabriel

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AU - Niklison Chirou, Maria

AU - Lim, Yau Mun

AU - Brandner, Sebastian

AU - Pollard, Steven M.

AU - Bennett, Christopher D.

AU - Clifford, Steven C.

AU - Peet, Andrew

AU - Basson, Albert

AU - Marino, Silvia

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AB - 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.

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JO - Nature Communications

JF - Nature Communications

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ER -

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

Abstract

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