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

Yinghua Li, Bo Li, Wei Li, Yuan Wang, Seçkin Akgül, 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 and Yuan Zhu ()
Additional contact information
Yinghua Li: Gilbert Family Neurofibromatosis Institute, Children’s National Hospital
Bo Li: University of Michigan Medical School
Wei Li: Center for Genetic Medicine Research, Children’s National Hospital
Yuan Wang: Gilbert Family Neurofibromatosis Institute, Children’s National Hospital
Seçkin Akgül: Gilbert Family Neurofibromatosis Institute, Children’s National Hospital
Daniel M. Treisman: Gilbert Family Neurofibromatosis Institute, Children’s National Hospital
Kevin A. Heist: University of Michigan Medical School
Brianna R. Pierce: Gilbert Family Neurofibromatosis Institute, Children’s National Hospital
Benjamin Hoff: University of Michigan Medical School
Cheng-Ying Ho: Center for Genetic Medicine Research, Children’s National Hospital
David O. Ferguson: University of Michigan Medical School
Alnawaz Rehemtulla: University of Michigan Medical School
Siyuan Zheng: The University of Texas Health Science Center at San Antonio
Brian D. Ross: University of Michigan Medical School
Jun Z. Li: University of Michigan Medical School
Yuan Zhu: Gilbert Family Neurofibromatosis Institute, Children’s National Hospital

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17382-3

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