VC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance
Cathy Pichol-Thievend, Océane Anezo, Aafrin M. Pettiwala, G Bourmeau, Rémi Montagne, Anne-Marie Lyne, Pierre‐Olivier Guichet, Pauline Deshors, Alberto Ballestín, Benjamin S. Blanchard, J Reveilles, Vidhya M. Ravi, Kevin Joseph, Dieter Henrik Heiland, Boris Julien, Sophie Leboucher, Laetitia Besse, Patricia Legoix, Florent Dingli, Stéphane Liva, Damarys Loew, Elisa Giani, Valentino Ribecco, Charita Furumaya, Laura Marcos-Kovandzic, Konstantin Masliantsev, Thomas Daubon, Lin Wang, Aarón Díaz, Oliver Schnell, Jürgen Beck, Nicolas Servant, Lucie Karayan‐Tapon, Florence M.G. Cavalli, Giorgio Seano
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.