Murine models of IDH-wild-type glioblastoma exhibit spatial segregation of tumor initiation and manifestation during evolution.

Nature Communications
Yinghua LiYuan Zhu

Abstract

Recent characterization of spatiotemporal genomic architecture of IDH-wild-type multifocal glioblastomas (M-GBMs) suggests a clinically unobserved common-ancestor (CA) with a less aggressive phenotype, generating highly genetically divergent malignant gliomas/GBMs in distant brain regions. Using serial MRI/3D-reconstruction, whole-genome sequencing and spectral karyotyping-based single-cell phylogenetic tree building, we show two distinct types of tumor evolution in p53-mutant driven mouse models. Malignant gliomas/GBMs grow as a single mass (Type 1) and multifocal masses (Type 2), respectively, despite both exhibiting loss of Pten/chromosome 19 (chr19) and PI3K/Akt activation with sub-tetraploid/4N genomes. Analysis of early biopsied and multi-segment tumor tissues reveals no evidence of less proliferative diploid/2N lesions in Type 1 tumors. Strikingly, CA-derived relatively quiescent tumor precursors with ancestral diploid/2N genomes and normal Pten/chr19 are observed in the subventricular zone (SVZ), but are distantly segregated from multi focal Type 2 tumors. Importantly, PI3K/Akt inhibition by Rictor/mTORC2 deletion blocks distant dispersal, restricting glioma growth in the SVZ.

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Citations

Sep 30, 2021·Nature Reviews. Cancer·Brian M AndersenFrancisco J Quintana

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Methods Mentioned

BETA
targeted mutations
biopsies
biopsy
Genotyping
PCR
PCRs
flow cytometry
chromosomal aberration

Software Mentioned

R
ANNOVAR
Matlab scripts
SAMtools
MATLAB
VnmrJ
FREEC
FlowJo
Burrows Aligner
Adobe photoshop

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