Murine models of IDH-wild-type glioblastoma exhibit spatial segregation of tumor initiation and manifestation during evolution.
Yinghua LiBo LiWei LiZhongwang WangSeçkin AkgülDaniel M TreismanKevin A HeistBrianna R PierceBenjamin HoffCheng-Ying HoDavid O FergusonAlnawaz RehemtullaSiyuan ZhengBrian D RossJun Z LiYuan ZhuPublished in: Nature communications (2020)
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.
Keyphrases
- pi k akt
- wild type
- signaling pathway
- cell proliferation
- cell cycle arrest
- single cell
- high grade
- lymph node
- magnetic resonance imaging
- mouse model
- computed tomography
- copy number
- gene expression
- high throughput
- optical coherence tomography
- multiple sclerosis
- contrast enhanced
- resting state
- white matter
- dna methylation
- cell death
- diffusion weighted imaging
- functional connectivity
- cerebral ischemia
- dual energy