The Dynamic UPR Rheostat Orchestrates Single-Cell Plasticity in Glioblastoma

Area of Science:

• Neuroscience
• Molecular Biology
• Genomics

Background:

• Glioblastoma (GBM) utilizes the unfolded protein response (UPR) to survive microenvironmental stress.
• The coordinated function of the three UPR arms (IRE1/XBP1, ATF6, PERK) in GBM at single-cell resolution is not fully understood.

Purpose of the Study:

• To investigate the single-cell resolution activity and coordination of the three canonical UPR arms in Glioblastoma.
• To characterize the UPR as a graded control system governing GBM cellular plasticity and stress tolerance.

Main Methods:

• Reanalysis of publicly available scRNA-seq datasets (discovery and validation cohorts).
• Development and application of arm-resolved metrics, including Rheostat Index and balance.
• Analysis of dynamic dominance switching of UPR arms along lineage trajectories.
• Statistical validation using transcription factor activity inference and patient-level inference via pseudobulk summaries.

Main Results:

• The UPR operates as a graded rheostat in GBM, with dynamic dominance switching observed (ATF6 early, IRE1 late, PERK rare).
• IRE1 and ATF6 show tight coupling, while PERK acts semi-independently, suggesting an adaptive division of labor.
• Rheostat tuning correlates with hypoxia and glycolytic programs and is consistent across different platforms and datasets.

Conclusions:

• The UPR functions as an arm-resolved rheostat, crucial for GBM cellular plasticity and stress adaptation.
• Findings suggest therapeutic strategies targeting UPR rebalancing, attenuating survival signaling (IRE1/ATF6) while allowing death pathways (PERK).
• Further functional validation with perturbation studies and protein-level readouts is warranted.