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

被引：25

作者：

Badodi, Sara ^{[1
]}

Pomella, Nicola ^{[1
]}

Zhang, Xinyu ^{[1
]}

Rosser, Gabriel ^{[1
]}

Whittingham, John ^{[2
]}

Niklison-Chirou, Maria Victoria ^{[1
,11
]}

Lim, Yau Mun ^{[3
,4
]}

Brandner, Sebastian ^{[3
,4
]}

Morrison, Gillian ^{[5
,6
]}

Pollard, Steven M. ^{[5
,6
]}

Bennett, Christopher D. ^{[7
,8
]}

Clifford, Steven C. ^{[9
]}

Peet, Andrew ^{[7
,8
]}

Basson, M. Albert ^{[2
,10
]}

Marino, Silvia ^{[1
]}

机构：

[1] Queen Mary Univ London, Blizard Inst, Barts & London Sch Med & Dent, London, England

[2] Kings Coll London, Ctr Craniofacial & Regenerat Biol, London, England

[3] Univ Coll London Hosp NHS Fdn Trust, UCL Queen Sq Inst Neurol, London, England

[4] Univ Coll London Hosp NHS Fdn Trust, Natl Hosp Neurol & Neurosurg, London, England

[5] Univ Edinburgh, Ctr Regenerat Med, Edinburgh, Midlothian, Scotland

[6] Univ Edinburgh, Canc Res UK Edinburgh Ctr, Edinburgh, Midlothian, Scotland

[7] Univ Birmingham, Inst Canc & Genom Sci, Birmingham, W Midlands, England

[8] Birmingham Women & Childrens Hosp, Birmingham, W Midlands, England

[9] Newcastle Univ, Ctr Canc, Wolfson Childhood Canc Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England

[10] Kings Coll London, MRC Ctr Neurodev Disorders, London, England

[11] Univ Bath, Dept Pharm & Pharmacol, Ctr Therapeut Innovat CTI Bath, Bath, Avon, England

来源：

NATURE COMMUNICATIONS | 2021年 / 12卷 / 01期

基金：

英国医学研究理事会;

关键词：

R/BIOCONDUCTOR PACKAGE; CEREBELLAR DEVELOPMENT; MOLECULAR SUBGROUPS; SIGNALING PATHWAY; HEXAPHOSPHATE IP6; MOUSE MODELS; CANCER; KINASE; BMI1; GENE;

D O I：

10.1038/s41467-021-22379-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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

引用

页数：16

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