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

Nat Commun. 2020 Jul 22;11(1):3669. doi: 10.1038/s41467-020-17382-3.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biopsy
  • Brain / diagnostic imaging
  • Brain / pathology
  • Brain Neoplasms / diagnostic imaging
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology
  • Carcinogenesis / genetics*
  • Clonal Evolution*
  • DNA Copy Number Variations
  • Disease Models, Animal
  • Evolution, Molecular*
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / diagnostic imaging
  • Glioblastoma / genetics*
  • Glioblastoma / pathology
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Karyotyping
  • Magnetic Resonance Imaging
  • Mechanistic Target of Rapamycin Complex 2 / genetics
  • Mice
  • Mice, Transgenic
  • Mutation
  • PTEN Phosphohydrolase / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rapamycin-Insensitive Companion of mTOR Protein / genetics
  • Signal Transduction / genetics
  • Single-Cell Analysis
  • Whole Genome Sequencing

Substances

  • Rapamycin-Insensitive Companion of mTOR Protein
  • rictor protein, mouse
  • Isocitrate Dehydrogenase
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • Pten protein, mouse