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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月29日

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  • 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

摘要

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.