TY - JOUR
T1 - Single-cell analyses reveal YAP/TAZ as regulators of stemness and cell plasticity in glioblastoma
AU - Castellan, Martina
AU - Guarnieri, Alberto
AU - Fujimura, Atsushi
AU - Zanconato, Francesca
AU - Battilana, Giusy
AU - Panciera, Tito
AU - Sladitschek, Hanna Lucie
AU - Contessotto, Paolo
AU - Citron, Anna
AU - Grilli, Andrea
AU - Romano, Oriana
AU - Bicciato, Silvio
AU - Fassan, Matteo
AU - Porcù, Elena
AU - Rosato, Antonio
AU - Cordenonsi, Michelangelo
AU - Piccolo, Stefano
N1 - Funding Information:
We thank I. Verma, J. Massagué and L. Naldini for plasmids and colleagues sharing their plasmids through Addgene (M.-C. Hung, L. Pedersen, C. Counter, C. Cepko, K. Hochedlinger and M. Meyerson). We thank D.J. Pan, D. Saur, J. Siveke and P. Bonaldo for gifts of mice, G. Basso for HuTu cells, G. Zuccolotto for the GFP/Luc-expressing lentiviral construct, V. Barbieri for in vivo experiments, V. Guzzardo for histology, S. Bresolin for microarrays, G. Leo for TAZ IHC analysis and M. Forcato for comments. M. Castellan was supported by a FIRC-AIRC fellowship for Italy. O.R. is supported by Fondazione Umberto Veronesi (Post-Doctoral Fellowship 2020). The research leading to these results has received funding from AIRC 5×1000 2018 ‘Metastasis as mechanodisease’ (ID, 22759) grant to S.P.; from AIRC IG Grant 2019 (ID, 23307) to S.P.; from the Italian Ministry of Education, University and Research under a MIUR-FARE grant to S.P. and a MIUR-PRIN Bando 2017 grant to S.P. (cod. 2017HWTP2K); from the European Research Council under the European Union’s Horizon 2020 research and innovation program (DENOVOSTEM grant agreement No 670126) to S.P.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. part of Springer Nature.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85097227757&partnerID=8YFLogxK
U2 - 10.1038/s43018-020-00150-z
DO - 10.1038/s43018-020-00150-z
M3 - Article
C2 - 33644767
AN - SCOPUS:85097227757
VL - 2
SP - 174
EP - 188
JO - Nature Cancer
JF - Nature Cancer
SN - 2662-1347
IS - 2
ER -
