4.8 Article

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

期刊

CELL REPORTS
卷 36, 期 10, 页码 -

出版社

CELL PRESS
DOI: 10.1016/j.celrep.2021.109673

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资金

  1. Spanish Ministerio de Ciencia e Innovacion [SAF2008-03238, SAF2011-29403]
  2. Comunidad de Madrid [S2013/ABI-2906-FEDER]
  3. Spanish Ministerio de Economia y Competitividad and Ministerio de Ciencia, Investigacion y Universidades [SAF2015-68522-P-MINECO/FEDER,UE]
  4. Banco Santander
  5. Fundacion Ramon Areces

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This study delves into the genetic and functional heterogeneity of human glioblastoma stem cells in response to non-pathogenic mouse parvoviruses. The study reveals that the viral NS1 protein triggers DNA damage response and cell cycle arrest in GSCs, potentially opening up new possibilities for viral therapies against glioblastoma.
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/eIF2a-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.

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