Metabolic rewiring induces a viral mimicry-mediated quiescence in glioblastoma
- 1The Hospital for Sick Children
Abstract
Glioblastoma is a highly aggressive brain tumour driven by therapy-resistant glioblastoma stem cells (GSCs) that switch between dormant and proliferative states through poorly defined programs. In this study, we identify SAT1, encoding the rate-limiting polyamine-catabolic enzyme SSAT1, as enriched in quiescent GSCs, linking metabolic rewiring to dormancy. Pharmacologic induction of SSAT1 with the polyamine analogue N1,N11-Diethylnorspermine (DENSpm) triggers a chemoprotective, reversible growth arrest in patient-derived GSCs, independent of stemness, differentiation or senescence. SAT1-induced dormancy coincides with reduced eIF5A hypusination and global protein translation, and a marked rise in double-stranded RNA that activates type I interferon signalling. Knocking down the mitochondrial antiviral-signalling protein, essential for antiviral innate immunity, partially reverses this growth arrest, establishing viral mimicry as functionally required for dormancy. Single-cell and cohort analyses across GSCs and neural stem cells demonstrate that susceptibility to metabolically induced quiescence is set by an intrinsic inflammatory tone and lysosomal dependency, defining a context-dependent metabolic-immune axis which can be targeted to prevent GBM progression.
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BibTeX
@misc{chesnelong2026metabolic,
title = {{Metabolic rewiring induces a viral mimicry-mediated quiescence in glioblastoma}},
author = {C. Chesnelong and K. Desai and C. S. Charton and M. Kushida and C. Yu and P. Guilhamon and L. Lee and S. Agnihotri and P. B. Dirks},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.01.755088},
url = {https://www.biorxiv.org/content/10.64898/2026.10.01.755088v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Metabolic rewiring induces a viral mimicry-mediated quiescence in glioblastoma
AU - C. Chesnelong
AU - K. Desai
AU - C. S. Charton
AU - M. Kushida
AU - C. Yu
AU - P. Guilhamon
AU - L. Lee
AU - S. Agnihotri
AU - P. B. Dirks
PY - 2026
DA - 2026/10/01
PB - bioRxiv
DO - 10.64898/2026.10.01.755088
UR - https://www.biorxiv.org/content/10.64898/2026.10.01.755088v1
AB - Glioblastoma is a highly aggressive brain tumour driven by therapy-resistant glioblastoma stem cells (GSCs) that switch between dormant and proliferative states through poorly defined programs. In this study, we identify SAT1, encoding the rate-limiting polyamine-catabolic enzyme SSAT1, as enriched in quiescent GSCs, linking metabolic rewiring to dormancy. Pharmacologic induction of SSAT1 with the polyamine analogue N1,N11-Diethylnorspermine (DENSpm) triggers a chemoprotective, reversible growth arrest in patient-derived GSCs, independent of stemness, differentiation or senescence. SAT1-induced dormancy coincides with reduced eIF5A hypusination and global protein translation, and a marked rise in double-stranded RNA that activates type I interferon signalling. Knocking down the mitochondrial antiviral-signalling protein, essential for antiviral innate immunity, partially reverses this growth arrest, establishing viral mimicry as functionally required for dormancy. Single-cell and cohort analyses across GSCs and neural stem cells demonstrate that susceptibility to metabolically induced quiescence is set by an intrinsic inflammatory tone and lysosomal dependency, defining a context-dependent metabolic-immune axis which can be targeted to prevent GBM progression.
ER -