TY  - JOUR
AU  - Obacz, Joanna
AU  - Archambeau, Jérôme
AU  - Lafont, Elodie
AU  - Nivet, Manon
AU  - Martin, Sophie
AU  - Aubry, Marc
AU  - Voutetakis, Konstantinos
AU  - Pineau, Raphael
AU  - Boniface, Rachel
AU  - Sicari, Daria
AU  - Pelizzari-Raymundo, Diana
AU  - Ghukasyan, Gevorg
AU  - McGrath, Eoghan
AU  - Vlachavas, Efstathios-Iason
AU  - Le Gallo, Matthieu
AU  - Le Reste, Pierre Jean
AU  - Barroso, Kim
AU  - Fainsod-Levi, Tanya
AU  - Obiedat, Akram
AU  - Granot, Zvi
AU  - Tirosh, Boaz
AU  - Samal, Juhi
AU  - Pandit, Abhay
AU  - Négroni, Luc
AU  - Soriano, Nicolas
AU  - Monnier, Annabelle
AU  - Mosser, Jean
AU  - Chatziioannou, Aristotelis
AU  - Quillien, Véronique
AU  - Chevet, Eric
AU  - Avril, Tony
TI  - IRE1 endoribonuclease signaling promotes myeloid cell infiltration in glioblastoma.
JO  - Neuro-Oncology
VL  - 26
IS  - 5
SN  - 1522-8517
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DKFZ-2024-00944
SP  - 858 - 871
PY  - 2024
AB  - Intrinsic or environmental stresses trigger the accumulation of improperly folded proteins in the endoplasmic reticulum (ER), leading to ER stress. To cope with this, cells have evolved an adaptive mechanism named the unfolded protein response (UPR) which is hijacked by tumor cells to develop malignant features. Glioblastoma (GB), the most aggressive and lethal primary brain tumor, relies on UPR to sustain growth. We recently showed that IRE1 alpha (referred to IRE1 hereafter), 1 of the UPR transducers, promotes GB invasion, angiogenesis, and infiltration by macrophage. Hence, high tumor IRE1 activity in tumor cells predicts a worse outcome. Herein, we characterized the IRE1-dependent signaling that shapes the immune microenvironment toward monocytes/macrophages and neutrophils.We used human and mouse cellular models in which IRE1 was genetically or pharmacologically invalidated and which were tested in vivo. Publicly available datasets from GB patients were also analyzed to confirm our findings.We showed that IRE1 signaling, through both the transcription factor XBP1s and the regulated IRE1-dependent decay controls the expression of the ubiquitin-conjugating E2 enzyme UBE2D3. In turn, UBE2D3 activates the NFκB pathway, resulting in chemokine production and myeloid infiltration in tumors.Our work identifies a novel IRE1/UBE2D3 proinflammatory axis that plays an instrumental role in GB immune regulation.
KW  - Glioblastoma: pathology
KW  - Glioblastoma: metabolism
KW  - Humans
KW  - Mice
KW  - Endoribonucleases: metabolism
KW  - Endoribonucleases: genetics
KW  - Animals
KW  - Protein Serine-Threonine Kinases: metabolism
KW  - Protein Serine-Threonine Kinases: genetics
KW  - Signal Transduction
KW  - Brain Neoplasms: pathology
KW  - Brain Neoplasms: metabolism
KW  - Myeloid Cells: metabolism
KW  - Myeloid Cells: pathology
KW  - Unfolded Protein Response
KW  - Tumor Microenvironment
KW  - Tumor Cells, Cultured
KW  - Endoplasmic Reticulum Stress
KW  - ER stress (Other)
KW  - IRE1 (Other)
KW  - chemokines (Other)
KW  - glioblastoma (Other)
KW  - inflammation (Other)
KW  - Endoribonucleases (NLM Chemicals)
KW  - Protein Serine-Threonine Kinases (NLM Chemicals)
KW  - ERN1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38153426
C2  - pmc:PMC11066906
DO  - DOI:10.1093/neuonc/noad256
UR  - https://inrepo02.dkfz.de/record/290039
ER  -