TY  - JOUR
AU  - Foerster, Leo Carl
AU  - Kaya, Oguzhan
AU  - Wüst, Valentin
AU  - Danciu, Diana-Patricia
AU  - Akçay, Vuslat
AU  - Bekavac, Milica
AU  - Ziegler, Kevin Chris
AU  - Stinchcombe, Nina
AU  - Tang, Anna
AU  - Kleber, Susanne
AU  - Tang, Joceyln
AU  - Brunken, Jan
AU  - Lois-Bermejo, Irene
AU  - Gesteira-Perez, Noelia
AU  - Ma, Xiujian
AU  - Sadik, Ahmed
AU  - Le, Phuong Uyen
AU  - Petrecca, Kevin
AU  - Opitz, Christiane
AU  - Liu, Haikun
AU  - Wirtz, Christian Rainer
AU  - Goncalves, Angela
AU  - Marciniak-Czochra, Anna
AU  - Anders, Simon
AU  - Martin-Villalba, Ana
TI  - Cross-species comparison reveals therapeutic vulnerabilities halting glioblastoma progression.
JO  - Nature Communications
VL  - 16
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-01638
SP  - 7250
PY  - 2025
N1  - #EA:A290#LA:A290#
AB  - 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.
KW  - Glioblastoma: genetics
KW  - Glioblastoma: pathology
KW  - Glioblastoma: metabolism
KW  - Humans
KW  - Animals
KW  - Mice
KW  - DNA Methylation
KW  - Disease Progression
KW  - Brain Neoplasms: pathology
KW  - Brain Neoplasms: genetics
KW  - Brain Neoplasms: metabolism
KW  - Gene Expression Regulation, Neoplastic
KW  - Membrane Proteins: metabolism
KW  - Membrane Proteins: genetics
KW  - Neural Stem Cells: metabolism
KW  - Neural Stem Cells: pathology
KW  - Intercellular Signaling Peptides and Proteins: metabolism
KW  - Intercellular Signaling Peptides and Proteins: genetics
KW  - Cell Line, Tumor
KW  - Neoplastic Stem Cells: metabolism
KW  - Neoplastic Stem Cells: pathology
KW  - Female
KW  - Male
KW  - Species Specificity
KW  - Prognosis
KW  - Membrane Proteins (NLM Chemicals)
KW  - Intercellular Signaling Peptides and Proteins (NLM Chemicals)
KW  - SFRP1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40770193
DO  - DOI:10.1038/s41467-025-62528-w
UR  - https://inrepo02.dkfz.de/record/303402
ER  -