IMR Press / FBL / Volume 27 / Issue 1 / DOI: 10.31083/j.fbl2701035
Open Access Original Research
Canonical WNT pathway inhibition reduces ATP synthesis rates in glioblastoma stem cells
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1 Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center (DDZ), 40225 Düsseldorf, Germany
2 German Center for Diabetes Research (DZD), München-Neuherberg, 40225 Düsseldorf, Germany
3 Department of Endocrinology, Ghent University Hospital, 41045 Ghent, Belgium
4 Clinic of Neurosurgery, University Hospital Düsseldorf and Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany
5 Beijing Neurosurgical Institute, Capital Medical University, 100054 Beijing, China
6 Department of Neurosurgery, Canton Hospital Aarau, 5001 Aarau, Switzerland
7 Clinic for Neurosurgery, Medical Faculty and University Hospital Magdeburg, 39120 Magdeburg, Germany
8 Molecular and Experimental Surgery, Clinic for General, Visceral, Vascular, and Transplant Surgery, Medical Faculty and University Hospital Magdeburg, 39120 Magdeburg, Germany
9 Department of Neurology, Hadassah-Hebrew University Medical Center, Ein Kerem, 91120 Jerusalem, Israel
*Correspondence: (Ulf D. Kahlert); (Or Kakhlon)
These authors contributed equally.
Academic Editor: Graham Pawelec
Front. Biosci. (Landmark Ed) 2022, 27(1), 35;
Submitted: 30 September 2021 | Revised: 13 December 2021 | Accepted: 27 December 2021 | Published: 18 January 2022
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Background: The conserved stem cell signaling network canonical Wingless (WNT) plays important roles in development and disease. Aberrant activation of this pathway has been linked to tumor progression and resistance to therapy. Industry and academia have substantially invested in developing substances, which can efficiently and specifically block the WNT signaling pathway. However, a clear clinical proof of the efficacy of this approach is still missing. Studies on the metabolomics dysregulation of cancer cells have led to innovations in oncological diagnostics. In addition, modulation of cancer cell metabolome is at the base of promising clinical oncology trials currently underway. While onco-protein activation can have profound metabolic outcomes, the involvement of stem cell signals, such as the WNT pathway, in tumor cell metabolomics is yet insufficiently characterized. Material and methods: We determined live cell metabolism and bioenergetics in pathophysiological relevant, WNT-dependent glioblastoma stem cell (GSC) models. We quantified those parameters in cells with canonical WNT activity and in isogenic cells where WNT activity had been inhibited by short hairpin RNA against β-catenin. Furthermore, we applied computational analysis of RNA sequencing to verify our functional findings in independent GSCs cohorts. Results: The investigated collection of disease models allows the separation in tumors with low, moderate and high base line metabolic activity. Suppression of canonical WNT signaling led to significant reduction of total, mitochondrial, and glycolytic ATP production rates. Elevated canonical WNT transcription signature in GSCs positively correlated with transcription levels of mitochondrial ATP synthesis, whereas non-canonical WNT gene expression signature did not. Conclusion: The applied disease modeling technology allows the recapitulation of inter-tumoral heterogeneous metabolic properties of glioblastoma. Our data show for the first time that inhibition of canonical WNT signaling in alive GSCs functionally correlates with energy inhibition and glucose homeostasis. As this correlation occurs in GSCs from different transcriptional or epigenetic transcriptional subtypes, our results suggest that developing therapies directed against glycolysis/ATP-synthesis may be a promising strategy to overcome therapy resistance due to inter-tumoral heterogeneity and offers starting point to impair downstream signal WNT.

Tumor stem cells
Single cell RNA sequencing
Fig. 1.
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