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A SOX2-engineered epigenetic silencer factor represses the glioblastoma genetic program and restrains tumor development.
Benedetti, Valerio; Banfi, Federica; Zaghi, Mattia; Moll-Diaz, Raquel; Massimino, Luca; Argelich, Laura; Bellini, Edoardo; Bido, Simone; Muggeo, Sharon; Ordazzo, Gabriele; Mastrototaro, Giuseppina; Moneta, Matteo; Sessa, Alessandro; Broccoli, Vania.
Afiliação
  • Benedetti V; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Banfi F; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Zaghi M; CNR Institute of Neuroscience, 20129 Milan, Italy.
  • Moll-Diaz R; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Massimino L; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Argelich L; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Bellini E; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Bido S; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Muggeo S; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Ordazzo G; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Mastrototaro G; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Moneta M; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Sessa A; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
  • Broccoli V; Stem Cell and Neurogenesis Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
Sci Adv ; 8(31): eabn3986, 2022 08 05.
Article em En | MEDLINE | ID: mdl-35921410
ABSTRACT
Current therapies remain unsatisfactory in preventing the recurrence of glioblastoma multiforme (GBM), which leads to poor patient survival. By rational engineering of the transcription factor SOX2, a key promoter of GBM malignancy, together with the Kruppel-associated box and DNA methyltransferase3A/L catalytic domains, we generated a synthetic repressor named SOX2 epigenetic silencer (SES), which induces the transcriptional silencing of its original targets. By doing so, SES kills both glioma cell lines and patient-derived cancer stem cells in vitro and in vivo. SES expression, through local viral delivery in mouse xenografts, induces strong regression of human tumors and survival rescue. Conversely, SES is not harmful to neurons and glia, also thanks to a minimal promoter that restricts its expression in mitotically active cells, rarely present in the brain parenchyma. Collectively, SES produces a significant silencing of a large fraction of the SOX2 transcriptional network, achieving high levels of efficacy in repressing aggressive brain tumors.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Glioblastoma / Glioma Limite: Animals / Humans Idioma: En Revista: Sci Adv Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Itália

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Glioblastoma / Glioma Limite: Animals / Humans Idioma: En Revista: Sci Adv Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Itália