B06

Wnt signaling in the adult brain: Regulation healthy and malignant stem cells

Funding period: 2017-2029

Project B06

Project Leaders

Prof. Dr. Ana Martin-Villalba

 Project Leader B06

Abstract

Our previous work demonstrated that the quiescence state of healthy neural stem cells correlates with high cnWNT activity. This deep quiescence is maintained by a distinct DNA methylome. In healthy stem cells, exit of quiescence involves methylome remodeling and expression of Wnt antagonists sFRP1 and Notum. In malignant glioblastoma cells, forced sFRP1 expression remodels the DNA methylome, induces deep quiescence and extends survival in preclinical glioblastoma- models. Key questions remain about whether tumors compensate for SFRP1-induced quiescence via self-renewal, how stable this state is, and if the impact of Wnt modulatory strategy is influenced by the location of the tumor in the brain.

Project-related Publications

Cross-species comparison reveals therapeutic vulnerabilities halting glioblastoma progression

Foerster LC, Kaya O, Wüst V, Danciu DP, Akcay V, Bekavac M, Ziegler KC, Stinchcombe N, Tang A, Kleber S, Tang J, Brunken J, Lois-Bermejo I, Gesteira-Perez N, Ma X, Sadik A, Le PU, Petrecca K, Opitz CA, Liu H, Wirtz CR, Goncalves A, Marciniak-Czochra A, Anders S, Martin-Villalba A. Nat Commun. 2025 Aug 6;16(1):7250. doi: 10.1038/s41467-025-62528-w.

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Unraveling regulatory feedback mechanisms in adult neurogenesis through mathematical modelling

Danciu, DP., Klawe, F.Z., Kazarnikov, A., Femmer, L., Kostina, E., Martin-Villalba, A. and Marciniak-Czochra, A. Unraveling regulatory feedback mechanisms in adult neurogenesis through mathematical modelling. npj Syst Biol Appl 11, 82 (2025). doi:10.1038/s41540-025-00563-5

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DNA methylation controls stemness of astrocytes in health and ischaemia

Kremer LPM, Cerrizuela S, El-Sammak H, Al Shukairi ME, Ellinger T, Straub J, Korkmaz A, Volk K, Brunken J, Kleber S, Anders S, Martin-Villalba A. Nature. 2024 Oct;634(8033):415-423. doi: 10.1038/s41586-024-07898-9. Epub 2024 Sep 4. PMID: 39232166

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Quiescence Modulates Stem Cell Maintenance and Regenerative Capacity in the Aging Brain

Kalamakis G, Brüne D, Ravichandran S, Bolz J, Fan W, Ziebell F, Stiehl T, Catalá-Martinez F, Kupke J, Zhao S, Llorens-Bobadilla E, Bauer K, Limpert S, Berger B, Christen U, Schmezer P, Mallm JP, Berninger B, Anders S, Del Sol A, Marciniak-Czochra A, Martin-Villalba A. Cell. 2019 Mar 7;176(6):1407-1419.e14. PMID: 30827680

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Revealing age related changes of adult hippocampal neurogenesis using mathematical models

Ziebell F, Dehler S, Martin-Villalba A, Marciniak-Czochra A. Development. 2018 Jan 8;145(1):dev153544. doi: 10.1242/dev.153544. PMID: 29229768

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Loss of Dickkopf-1 Restores Neurogenesis in Old Age and Counteracts Cognitive Decline

Seib DR, Corsini NS, Ellwanger K, Plaas C, Mateos A, Pitzer C, Niehrs C, Celikel T, Martin-Villalba A. Cell Stem Cell. 2013 Feb 7;12(2):204-14. doi: 10.1016/j.stem.2012.11.010. PMID: 23395445

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