Single-nuclei UPR profiling by flow cytometry reveals bortezomib resistance mechanisms in multiple myeloma

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.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2026-06-29
DOI
https://doi.org/10.1038/s44321-026-00469-7
Primary Topic
Endoplasmic Reticulum Stress and Disease
Type
article
Field-Weighted Citation Impact
0.00

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article

Single-nuclei UPR profiling by flow cytometry reveals bortezomib resistance mechanisms in multiple myeloma

Rosario Lavignolle, Julien P. Gigan, Stéphane Rocchi, Rafael J. Argüello et al.
EMBO Molecular Medicine
Endoplasmic Reticulum Stress and Disease
article

Single-nuclei UPR profiling by flow cytometry reveals bortezomib resistance mechanisms in multiple myeloma

Rosario Lavignolle, Julien P. Gigan, Stéphane Rocchi, Rafael J. Argüello, Jérôme Moreaux, Caroline Bret, A Reynaud, Réjane Rua, Felipe Flores‐Santibáñez, Alessandro Bani, Béatrice Nal, Philippe Pierre, Evelina Gatti, Lou Galliot, Angelo Pilotti, Yoan Ghaffar, A Combes, Daniela Barros, Eve Seillier, Sara Ghafoori, Paulina Garcia-Gonzalez, Sharon Fichaux
article en

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.

EMBO Molecular Medicine
Centre National de la Recherche Scientifique (FR), Inserm (FR), University of California, San Francisco (US), Shanghai Jiao Tong University (CN), Université Côte d'Azur (FR), Aix-Marseille Université (FR), Institut de Génétique Humaine (FR), University of Aveiro (PT), University of San Francisco (US)
Transcan, European Commission, Agence Nationale de la Recherche, Fondation ARC pour la Recherche sur le Cancer, Institut National Du Cancer, National Cancer Institute, HORIZON EUROPE Marie Sklodowska-Curie Actions, HORIZON EUROPE Health
Good health and well-being
Openalex Percentile: Top 9%
Endoplasmic Reticulum Stress and Disease
DOIOpen Access PDFOpenAlex
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