Single-cell analyses reveal YAP/TAZ as regulators of stemness and cell plasticity in glioblastoma

Martina Castellan, Alberto Guarnieri, Atsushi Fujimura, Francesca Zanconato, Giusy Battilana, Tito Panciera, Hanna Lucie Sladitschek, Paolo Contessotto, Anna Citron, Andrea Grilli, Oriana Romano, Silvio Bicciato, Matteo Fassan, Elena Porcù, Antonio Rosato, Michelangelo Cordenonsi, Stefano Piccolo

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Glioblastoma (GBM) is a devastating human malignancy. GBM stem-like cells (GSCs) drive tumor initiation and progression. Yet the molecular determinants defining GSCs in their native state in patients remain poorly understood. Here we used single-cell datasets and identified GSCs at the apex of the differentiation hierarchy of GBM. By reconstructing the GSCs’ regulatory network, we identified the YAP/TAZ coactivators as master regulators of this cell state, irrespectively of GBM subtypes. YAP/TAZ are required to install GSC properties in primary cells downstream of multiple oncogenic lesions and are required for tumor initiation and maintenance in vivo in different mouse and human GBM models. YAP/TAZ act as main roadblock of GSC differentiation, and their inhibition irreversibly locks differentiated GBM cells into a nontumorigenic state, preventing plasticity and regeneration of GSC-like cells. Thus, GSC identity is linked to a key molecular hub integrating genetics and microenvironmental inputs within the multifaceted biology of GBM.

Original languageEnglish
Pages (from-to)174-188
Number of pages15
JournalNature Cancer
Volume2
Issue number2
DOIs
Publication statusPublished - Feb 2021
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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