Glioblastoma cells that evade chemoradiotherapy-induced cell death exhibit a bifurcated glycolytic program.

Overview

1. Department of Pathology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB Canada
2. Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB Canada
3. Pathology and Laboratory Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB Canada
4. Department of Surgery, McMaster University, Hamilton, ON Canada
5. Centre for Discovery in Cancer Research, McMaster University, Hamilton, ON Canada
6. PrairieNeuro Research Centre, Health Sciences Centre, Kleysen Institute for Advanced Medicine, Winnipeg, MB Canada
7. Department of Biochemistry, McMaster University, Hamilton, ON Canada
8. Paul Albrechtsen Research Institute, CancerCare Manitoba, Winnipeg, MB Canada

Abstract

Glioblastoma (GBM), the most common malignant brain tumor in adults, remains a highly lethal and incurable cancer, with a 5-year survival rate below 10%. Standard-of-care involves surgical resection followed by concurrent temozolomide chemotherapy and radiation treatment. While these interventions can effectively shrink tumors, they fail to eradicate all malignant cells. Small populations of GBM cells invariably survive and seed recurrent disease, leading to near-universal relapse and the formation of fatal recurrent tumors, typically within 1–2 years of treatment. Here, we investigated the metabolic features that define these surviving cell populations using ten patient-derived GBM models and matched orthotopic xenograft models exposed to a clinically relevant chemoradiotherapy regimen. By sampling living cells at defined treatment intervals and integrating 13C-glucose tracing, quantitative untargeted metabolomics, and nCounter metabolic gene expression profiling, we reconstructed the temporal evolution of glucose metabolism from therapy-naïve to post-treatment states. Across all models, GBM cells that evaded therapy-induced death exhibited a conserved and coordinated reorganization of glycolytic flux. These cells showed enhanced glucose uptake and elevated abundance of upper glycolytic enzymes such as HK1, while lower glycolytic enzymes, including ALDOA, GAPDH, ENO1, and LDHA, were suppressed, resulting in reduced lactate output. This bifurcation of glycolytic metabolism redirected carbon flux toward the pentose phosphate pathway and nucleotide biosynthesis, as well as mitochondrial metabolism, supported by the increased abundance of tricarboxylic acid cycle enzymes. Notably, these adaptations were conserved in recurrent patient-derived orthotopic xenograft tumors in vivo. Together, these findings reveal a fundamental and conserved metabolic state that defines GBM cells surviving chemoradiotherapy. This study deciphers a core metabolic architecture that enables tumor cell survival, persistence, and recurrence following therapy by shifting glycolytic flux away from lactate production to balance biosynthetic demands with mitochondrial metabolism.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE195681, at NCBI GEO; found in “Data availability”

Data availability

Raw files for untargeted metabolomics mass spectrometry data have been deposited to the Global Natural Products Molecular Networking (GNPS) repository [50] as a part of MassIVE (MSV000093877, 10.25345/C55D8NR5C). Data can be downloaded through the following FTP link: ftp://massive.ucsd.edu/MSV000093877/. This paper reports on previously published and publicly available datasets from Martell et al. [16] (10.1093/neuonc/noaf008) and Qazi et al. [29]. (GSE195681 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE195681)). All data generated or analyzed during this study are included in this manuscript and its supplementary information files. Original uncropped western blot images are source data are provided in the supplementary material. All other data reported in this paper will be shared by the lead contact upon request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 3 keywords, 12 MeSH terms, 4 funders, 50 references.

Cite

This paper

Martell, E., Kuzmychova, H., Chawla, U., Grewal, A., Jain, C., Venugopal, C., Anderson, C. M., Singh, S. K., & Sharif, T. (2026). Glioblastoma cells that evade chemoradiotherapy-induced cell death exhibit a bifurcated glycolytic program. Cell death & disease, 17(1), 348. https://doi.org/10.1038/s41419-026-08646-9

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