Dual IRE1 RNase functions dictate glioblastoma development

Stéphanie Lhomond (1) , Tony Avril (2) , Nicolas Dejeans (1) , Konstantinos Voutetakis (3) , Dimitrios Doultsinos (2) , Mari Mcmahon (2) , Raphael Pineau (2) , Joanna Obacz (2) , Olga Papadodima (3) , Florence Jouan (2) , Heloise Bourien (2) , Marianthi Logotheti (3) , Gwenaele Jegou (2) , Nestor Pallares-Lupon (1) , Kathleen Schmit (1) , Pierre-Jean Le Reste (2) , Amandine Etcheverry (4) , Jean Mosser (4) , Kim Barroso (2) , Elodie Vauléon (2) , Marion Maurel (2) , Afshin Samali (5) , John B. Patterson , Olivier Pluquet (6) , Claudio Hetz (7) , Véronique Quillien (2) , Aristotelis Chatziioannou (3) , Eric Chevet (2)

1 UB - Université de Bordeaux
2 COSS - Chemistry, Oncogenesis, Stress and Signaling
3 Theoretical and Physical Chemistry Institute NHRF
4 IGDR - Institut de Génétique et Développement de Rennes
5 NUI Galway - National University of Ireland [Galway]
6 M3T - Mécanismes de la Tumorigénèse et Thérapies Ciblées - UMR 8161
7 USACH - Universidad de Santiago de Chile [Santiago]

Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1 alpha (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1-dependent decay (RIDD) of RNA. Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1-dependent gene expression signatures that were confronted to human GBM transcriptomes. This approach allowed us to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor outcomes, mainly through selective remodeling of the tumor stroma. This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression.

Mots clés: cancer; endoplasmic reticulum; IRE1; regulated IRE1-dependent decay; XBP1

Domaines: Cancer; Chimie

Stéphanie Lhomond, Tony Avril, Nicolas Dejeans, Konstantinos Voutetakis, Dimitrios Doultsinos, et al.. Dual IRE1 RNase functions dictate glioblastoma development. EMBO Molecular Medicine, 2018, 10 (3), pp.e7929. ⟨10.15252/emmm.201707929⟩. ⟨hal-01777737⟩