Cross-species comparison reveals therapeutic vulnerabilities halting glioblastoma progression

Leo Carl Foerster, Oguzhan Kaya, Valentin Wüst, Diana-Patricia Danciu, Vuslat Akcay, Milica Bekavac, Kevin Chris Ziegler, Nina Stinchcombe, Anna Tang, Susanne Kleber, Joceyln Tang, Jan Brunken, Irene Lois-Bermejo, Noelia Gesteira-Perez, Xiujian Ma, Ahmed Sadik, Phuong Uyen Le, Kevin Petrecca, Christiane A. Opitz, Haikun Liu, Christian Rainer Wirtz, Angela Goncalves, Anna Marciniak-Czochra, Simon Anders and Ana Martin-Villalba ()
Additional contact information
Leo Carl Foerster: German Cancer Research Center (DKFZ)
Oguzhan Kaya: German Cancer Research Center (DKFZ)
Valentin Wüst: University of Heidelberg
Diana-Patricia Danciu: University of Heidelberg
Vuslat Akcay: German Cancer Research Center (DKFZ)
Milica Bekavac: German Cancer Research Center (DKFZ)
Kevin Chris Ziegler: German Cancer Research Center (DKFZ)
Nina Stinchcombe: German Cancer Research Center (DKFZ)
Anna Tang: University of Heidelberg
Susanne Kleber: German Cancer Research Center (DKFZ)
Joceyln Tang: German Cancer Research Center (DKFZ)
Jan Brunken: German Cancer Research Center (DKFZ)
Irene Lois-Bermejo: German Cancer Research Center (DKFZ)
Noelia Gesteira-Perez: German Cancer Research Center (DKFZ)
Xiujian Ma: German Cancer Research Center (DKFZ)
Ahmed Sadik: DKFZ Core Center Heidelberg
Phuong Uyen Le: McGill University
Kevin Petrecca: McGill University
Christiane A. Opitz: DKFZ Core Center Heidelberg
Haikun Liu: German Cancer Research Center (DKFZ)
Christian Rainer Wirtz: Ulm University Hospital
Angela Goncalves: German Cancer Research Center (DKFZ)
Anna Marciniak-Czochra: University of Heidelberg
Simon Anders: University of Heidelberg
Ana Martin-Villalba: German Cancer Research Center (DKFZ)

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract The growth of a tumor is tightly linked to the distribution of its cells along a continuum of activation states. Here, we systematically decode the activation state architecture (ASA) in a glioblastoma (GBM) patient cohort through comparison to adult murine neural stem cells. Modelling of these data forecasts how tumor cells organize to sustain growth and identifies the rate of activation as the main predictor of growth. Accordingly, patients with a higher quiescence fraction exhibit improved outcomes. Further, DNA methylation arrays enable ASA-related patient stratification. Comparison of healthy and malignant gene expression dynamics reveals dysregulation of the Wnt-antagonist SFRP1 at the quiescence to activation transition. SFRP1 overexpression renders GBM quiescent and increases the overall survival of tumor-bearing mice. Surprisingly, it does so through reprogramming the tumor’s stem-like methylome into an astrocyte-like one. Our findings offer a framework for patient stratification with prognostic value, biomarker identification, and therapeutic avenues to halt GBM progression.

Date: 2025
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DOI: 10.1038/s41467-025-62528-w

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