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
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 lock differentiated GBM cells into a non-tumorigenic
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.
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