EMBO Molecular Medicine (Mar 2018)
Dual IRE1 RNase functions dictate glioblastoma development
- Stéphanie Lhomond,
- Tony Avril,
- Nicolas Dejeans,
- Konstantinos Voutetakis,
- Dimitrios Doultsinos,
- Mari McMahon,
- Raphaël Pineau,
- Joanna Obacz,
- Olga Papadodima,
- Florence Jouan,
- Heloise Bourien,
- Marianthi Logotheti,
- Gwénaële Jégou,
- Néstor Pallares‐Lupon,
- Kathleen Schmit,
- Pierre‐Jean Le Reste,
- Amandine Etcheverry,
- Jean Mosser,
- Kim Barroso,
- Elodie Vauléon,
- Marion Maurel,
- Afshin Samali,
- John B Patterson,
- Olivier Pluquet,
- Claudio Hetz,
- Véronique Quillien,
- Aristotelis Chatziioannou,
- Eric Chevet
Affiliations
- Stéphanie Lhomond
- Université de Bordeaux Bordeaux France
- Tony Avril
- INSERM U1242, “Chemistry, Oncogenesis, Stress, Signaling” Université de Rennes 1 Rennes France
- Nicolas Dejeans
- Université de Bordeaux Bordeaux France
- Konstantinos Voutetakis
- Institute of Biology, Medicinal Chemistry & Biotechnology NHRF Athens Greece
- Dimitrios Doultsinos
- INSERM U1242, “Chemistry, Oncogenesis, Stress, Signaling” Université de Rennes 1 Rennes France
- Mari McMahon
- INSERM U1242, “Chemistry, Oncogenesis, Stress, Signaling” Université de Rennes 1 Rennes France
- Raphaël Pineau
- INSERM U1242, “Chemistry, Oncogenesis, Stress, Signaling” Université de Rennes 1 Rennes France
- Joanna Obacz
- INSERM U1242, “Chemistry, Oncogenesis, Stress, Signaling” Université de Rennes 1 Rennes France
- Olga Papadodima
- Institute of Biology, Medicinal Chemistry & Biotechnology NHRF Athens Greece
- Florence Jouan
- INSERM U1242, “Chemistry, Oncogenesis, Stress, Signaling” Université de Rennes 1 Rennes France
- Heloise Bourien
- INSERM U1242, “Chemistry, Oncogenesis, Stress, Signaling” Université de Rennes 1 Rennes France
- Marianthi Logotheti
- Institute of Biology, Medicinal Chemistry & Biotechnology NHRF Athens Greece
- Gwénaële Jégou
- INSERM U1242, “Chemistry, Oncogenesis, Stress, Signaling” Université de Rennes 1 Rennes France
- Néstor Pallares‐Lupon
- Université de Bordeaux Bordeaux France
- Kathleen Schmit
- Université de Bordeaux Bordeaux France
- Pierre‐Jean Le Reste
- INSERM U1242, “Chemistry, Oncogenesis, Stress, Signaling” Université de Rennes 1 Rennes France
- Amandine Etcheverry
- Integrated Functional Genomics and Biomarkers Team UMR6290, CNRS Université de Rennes 1 Rennes France
- Jean Mosser
- Integrated Functional Genomics and Biomarkers Team UMR6290, CNRS Université de Rennes 1 Rennes France
- Kim Barroso
- INSERM U1242, “Chemistry, Oncogenesis, Stress, Signaling” Université de Rennes 1 Rennes France
- Elodie Vauléon
- INSERM U1242, “Chemistry, Oncogenesis, Stress, Signaling” Université de Rennes 1 Rennes France
- Marion Maurel
- INSERM U1242, “Chemistry, Oncogenesis, Stress, Signaling” Université de Rennes 1 Rennes France
- Afshin Samali
- Apoptosis Research Centre School of Natural Sciences NUI Galway Galway Ireland
- John B Patterson
- Medinnovata Inc. Ventura CA USA
- Olivier Pluquet
- Institut Pasteur de Lille CNRS UMR8161 “Mechanisms of Tumourigenesis and Targeted Therapies” Université de Lille Lille France
- Claudio Hetz
- Biomedical Neuroscience Institute Faculty of Medicine University of Chile Santiago Chile
- Véronique Quillien
- INSERM U1242, “Chemistry, Oncogenesis, Stress, Signaling” Université de Rennes 1 Rennes France
- Aristotelis Chatziioannou
- Institute of Biology, Medicinal Chemistry & Biotechnology NHRF Athens Greece
- Eric Chevet
- INSERM U1242, “Chemistry, Oncogenesis, Stress, Signaling” Université de Rennes 1 Rennes France
- DOI
- https://doi.org/10.15252/emmm.201707929
- Journal volume & issue
-
Vol. 10,
no. 3
pp. n/a – n/a
Abstract
Abstract 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 IRE1α (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.
Keywords