VC-resist glioblastoma cell state: vessel co-option as a key driver of chemoradiation resistance
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
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Notes
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Nature Communications. - 15, 1 (2024) , 3602, ISSN: 2041-1723
- Event
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Veröffentlichung
- (where)
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Freiburg
- (who)
-
Universität
- (when)
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2024
- Creator
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Pichol-Thievend, Cathy
Anezo, Oceane
Pettiwala, Aafrin M.
Ravi, Vidhya M.
Joseph, Kevin
Heiland, Dieter Henrik
Schnell, Oliver
Beck, Jürgen
Seano, Giorgio
- DOI
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10.1038/s41467-024-47985-z
- URN
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urn:nbn:de:bsz:25-freidok-2494537
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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14.08.2025, 10:48 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Pichol-Thievend, Cathy
- Anezo, Oceane
- Pettiwala, Aafrin M.
- Ravi, Vidhya M.
- Joseph, Kevin
- Heiland, Dieter Henrik
- Schnell, Oliver
- Beck, Jürgen
- Seano, Giorgio
- Universität
Time of origin
- 2024
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