Murine Models of IDH-wild-type Glioblastoma Exhibit Spatial Segregation of Tumor Initiation and Manifestation During Evolution

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Jul 24

PMID 32699356

Citations 12

Authors

YingHua Li

Bo Li

Wei Li

Yuan Wang

Seckin Akgul

Daniel M Treisman

Kevin A Heist

Brianna R Pierce

Benjamin Hoff

Cheng-Ying Ho

David O Ferguson

Alnawaz Rehemtulla

Siyuan Zheng

Brian D Ross

Jun Z Li

Yuan Zhu

Affiliations

Soon will be listed here.

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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