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

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.SAF2008-03238 and SAF2011-29403 (Spanish Ministerio de Ciencia e Innovacion), S2013/ABI-2906-FEDER (Comunidad de Madrid), and SAF2015-68522-P-MINECO/FEDER,UE (Spanish Ministerio de Economía y Competitividad and Ministerio de Ciencia, Investigación y Universidades) to J.M.A. The Centro de Biología Molecular Severo Ochoa (CSIC-UAM) is, in part, supported by institutional grants from Banco Santander and Fundación Ramón Areces