Viral targeting of glioblastoma stem cells with patient-specific genetic and post-translational p53 deregulations

Cell Rep. 2021 Sep 7;36(10):109673. doi: 10.1016/j.celrep.2021.109673.


Cancer therapy urges targeting of malignant subsets within self-renewing heterogeneous stem cell populations. We dissect the genetic and functional heterogeneity of human glioblastoma stem cells (GSCs) within patients by their innate responses to non-pathogenic mouse parvoviruses that are tightly restrained by cellular physiology. GSC neurospheres accumulate assembled capsids but restrict viral NS1 cytotoxic protein expression by an innate PKR/eIF2α-P response counteractable by electric pulses. NS1 triggers a comprehensive DNA damage response involving cell-cycle arrest, neurosphere disorganization, and bystander disruption of GSC-derived brain tumor architecture in rodent models. GSCs and cancer cell lines permissive to parvovirus genome replication require p53-Ser15 phosphorylation (Pp53S15). NS1 expression is enhanced by exogeneous Pp53S15 induction but repressed by wtp53. Consistently, patient-specific GSC subpopulations harboring p53 gain-of-function mutants and/or Pp53S15 are selective viral targets. This study provides a molecular foundation for personalized biosafe viral therapies against devastating glioblastoma and other cancers with deregulated p53 signaling.

Keywords: DDR; PKR; brain tumor MRI; cancer virotherapy; genetic heterogeneity; glioblastoma stem cells; neurospheres; p53 GOF mutants; p53-Ser15 phosphorylation; parvovirus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology*
  • Cell Line, Tumor
  • Glioblastoma / pathology
  • Glioblastoma / virology*
  • Humans
  • Neoplastic Stem Cells / metabolism*
  • Phosphorylation
  • Rats
  • Rats, Nude
  • Signal Transduction / physiology
  • Tumor Suppressor Protein p53 / metabolism*
  • Virus Replication / physiology


  • Tumor Suppressor Protein p53