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

Cathy Pichol-Thievend (1) , Oceane Anezo (1) , Aafrin Pettiwala (1, 2) , Guillaume Bourmeau (1) , Remi Montagne (2, 3, 4) , Anne-Marie Lyne (2, 3, 4) , Pierre-Olivier Guichet (5, 6) , Pauline Deshors (1) , Alberto Ballestín (1) , Benjamin Blanchard (1) , Juliette Reveilles (1) , Vidhya Ravi (7) , Kevin Joseph (7) , Dieter Heiland (7) , Boris Julien (1) , Sophie Leboucher (8) , Laetitia Besse (9) , Patricia Legoix (2) , Florent Dingli (10, 11) , Stephane Liva (3, 4) , Damarys Loew (10, 11) , Elisa Giani (12) , Valentino Ribecco (1) , Charita Furumaya (1) , Laura Marcos-Kovandzic (1) , Konstantin Masliantsev (5, 6) , Thomas Daubon (13) , Lin Wang (14) , Aaron Diaz (15) , Oliver Schnell (7) , Jürgen Beck (7) , Nicolas Servant (3, 4) , Lucie Karayan-Tapon (5, 6) , Florence Cavalli (3, 4) , Giorgio Seano (1)

1 Signalisation, radiobiologie et cancer
2 Institut Curie [Paris]
3 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
4 CBIO - Centre de Bioinformatique
5 Prodicet [Poitiers] - Progression et dissémination cérébrales des cellules tumorales
6 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
7 University of Freiburg [Freiburg]
8 Institut Curie Centre de Protonthérapie d'Orsay
9 MIC - Multimodal Imaging Center (Centre d'Imagerie Multimodale)
10 RadeXp - CurieCoreTech-Experimental Radiotherapy
11 Laboratoire de Spectrométrie de Masse Protéomique
12 Hunimed - Humanitas University [Milan]
13 IBGC - Institut de biochimie et génétique cellulaires
14 Beckman Research Institute of the City of Hope
15 UC San Francisco - University of California [San Francisco]

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.

Domaines: Cancer; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Médecine nucléaire; Neurobiologie

Cathy Pichol-Thievend, Oceane Anezo, Aafrin Pettiwala, Guillaume Bourmeau, Remi Montagne, et al.. VC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance. Nature Communications, 2024, 15 (1), pp.3602. ⟨10.1038/s41467-024-47985-z⟩. ⟨hal-04648492⟩