Single-nuclei UPR profiling by flow cytometry reveals bortezomib resistance mechanisms in multiple myeloma
Year: 2026
Type: article
Abstract: The unfolded protein response (UPR) is a stress-adaptation pathway and therapeutic target in cancer, yet its pro-survival versus pro-death outcome is difficult to predict because the three ER sensors, PERK, IRE1α, and ATF6, are highly interconnected. Transcriptomic analyses identified sensor-specific gene signatures associated with patient survival across malignancies, and indicated that low IRE1α activity (low XBP1 signature or higher expression of RIDD targets) correlates with improved outcome. We developed SNUPR (single nuclei analysis of the unfolded protein response), an accessible flow cytometry approach that profiles all three branches in nuclear suspensions. SNUPR reveals marked heterogeneity of UPR activation across cancer cell lines that cannot be inferred from sensor expression. This heterogeneity is derived from differences in the strength and duration of PERK-mediated translational inhibition, which gates downstream translation-dependent IRE1α and ATF6 transcriptional programs. Finally, in multiple myeloma, we show that bortezomib-tolerant cells depend on IRE1α activity for survival, linking UPR state to proteasome-inhibitor resistance and positioning SNUPR to guide branch-selective targeting.
Source: EMBO Molecular Medicine
Authors: Julien P Gigan, Paulina Garcia-Gonzalez, Angelo Pilotti, Lou Galliot, Alexandre Reynaud, Yoan Ghaffar, Felipe Flores-Santibáñez, Sara Ghafoori, Eve Seillier, Rosario Lavignolle-Heguy, Daniela Barros, Caroline Bret, Sharon Fichaux, Alexis Combes, Alessandro Bani, Rejane Rua, Evelina Gatti, Béatrice Nal-Rogier, Stéphane Rocchi, Jérôme Moreaux, Philippe Pierre, Rafael J Argüello
Institutions: Centre National de la Recherche Scientifique, Inserm, Aix-Marseille Université, Centre d’Immunologie de Marseille-Luminy, University of Aveiro, University of California, San Francisco, Université Côte d'Azur, Centre Méditerranéen de Médecine Moléculaire, Institut de Génétique Humaine, Shanghai Jiao Tong University, Shanghai Institute of Immunology
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $7,990
OpenAlex ID: W7166591983