VC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance

Cathy Pichol-Thievend, Oceane Anezo, Aafrin M. Pettiwala, Guillaume Bourmeau, Remi Montagne, Anne-Marie Lyne, Pierre-Olivier Guichet, Pauline Deshors, Alberto Ballestín, Benjamin Blanchard, Juliette Reveilles, Vidhya M. Ravi, Kevin Joseph, Dieter H. Heiland, Boris Julien, Sophie Leboucher, Laetitia Besse, Patricia Legoix, Florent Dingli, Stephane Liva, Damarys Loew, Elisa Giani, Valentino Ribecco, Charita Furumaya, Laura Marcos-Kovandzic, Konstantin Masliantsev, Thomas Daubon, Lin Wang, Aaron A. Diaz, Oliver Schnell, Jürgen Beck, Nicolas Servant, Lucie Karayan-Tapon, Florence M. G. Cavalli and Giorgio Seano ()
Additional contact information
Cathy Pichol-Thievend: Paris-Saclay University
Oceane Anezo: Paris-Saclay University
Aafrin M. Pettiwala: Paris-Saclay University
Guillaume Bourmeau: Paris-Saclay University
Remi Montagne: PSL University
Anne-Marie Lyne: PSL University
Pierre-Olivier Guichet: ProDiCeT
Pauline Deshors: Paris-Saclay University
Alberto Ballestín: Paris-Saclay University
Benjamin Blanchard: Paris-Saclay University
Juliette Reveilles: Paris-Saclay University
Vidhya M. Ravi: Medical Center - University of Freiburg
Kevin Joseph: Medical Center - University of Freiburg
Dieter H. Heiland: Medical Center - University of Freiburg
Boris Julien: Paris-Saclay University
Sophie Leboucher: Institut Curie
Laetitia Besse: Multimodal Imaging Center
Patricia Legoix: ICGex Next-Generation Sequencing Platform
Florent Dingli: CurieCoreTech Spectrométrie de Masse Protéomique
Stephane Liva: PSL University
Damarys Loew: CurieCoreTech Spectrométrie de Masse Protéomique
Elisa Giani: Humanitas University
Valentino Ribecco: Paris-Saclay University
Charita Furumaya: Paris-Saclay University
Laura Marcos-Kovandzic: Paris-Saclay University
Konstantin Masliantsev: ProDiCeT
Thomas Daubon: UMR5095
Lin Wang: City of Hope
Aaron A. Diaz: University of California, San Francisco
Oliver Schnell: Medical Center - University of Freiburg
Jürgen Beck: Medical Center - University of Freiburg
Nicolas Servant: PSL University
Lucie Karayan-Tapon: ProDiCeT
Florence M. G. Cavalli: PSL University
Giorgio Seano: Paris-Saclay University

Nature Communications, 2024, vol. 15, issue 1, 1-27

Abstract: Abstract Glioblastoma (GBM) is a highly lethal type of cancer. GBM recurrence following chemoradiation is typically attributed to the regrowth of invasive and resistant cells. Therefore, there is a pressing need to gain a deeper understanding of the mechanisms underlying GBM resistance to chemoradiation and its ability to infiltrate. Using a combination of transcriptomic, proteomic, and phosphoproteomic analyses, longitudinal imaging, organotypic cultures, functional assays, animal studies, and clinical data analyses, we demonstrate that chemoradiation and brain vasculature induce cell transition to a functional state named VC-Resist (vessel co-opting and resistant cell state). This cell state is midway along the transcriptomic axis between proneural and mesenchymal GBM cells and is closer to the AC/MES1-like state. VC-Resist GBM cells are highly vessel co-opting, allowing significant infiltration into the surrounding brain tissue and homing to the perivascular niche, which in turn induces even more VC-Resist transition. The molecular and functional characteristics of this FGFR1-YAP1-dependent GBM cell state, including resistance to DNA damage, enrichment in the G2M phase, and induction of senescence/stemness pathways, contribute to its enhanced resistance to chemoradiation. These findings demonstrate how vessel co-option, perivascular niche, and GBM cell plasticity jointly drive resistance to therapy during GBM recurrence.

Date: 2024
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DOI: 10.1038/s41467-024-47985-z

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