Journal Article

DKFZ-2024-00944

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png IRE1 endoribonuclease signaling promotes myeloid cell infiltration in glioblastoma.

Obacz, J. ; Archambeau, J. ; Lafont, E. ; Nivet, M. ; Martin, S. ; Aubry, M. ; Voutetakis, K. ; Pineau, R. ; Boniface, R. ; Sicari, D. ; Pelizzari-Raymundo, D. ; Ghukasyan, G. ; McGrath, E. ; Vlachavas, E.-I.DKFZ* ; Le Gallo, M. ; Le Reste, P. J. ; Barroso, K. ; Fainsod-Levi, T. ; Obiedat, A. ; Granot, Z. ; Tirosh, B. ; Samal, J. ; Pandit, A. ; Négroni, L. ; Soriano, N. ; Monnier, A. ; Mosser, J. ; Chatziioannou, A.DKFZ* ; Quillien, V. ; Chevet, E. ; Avril, T.

2024
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/neuonc/noad256

Abstract: 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.

Keyword(s): Glioblastoma: pathology (MeSH) ; Glioblastoma: metabolism (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Endoribonucleases: metabolism (MeSH) ; Endoribonucleases: genetics (MeSH) ; Animals (MeSH) ; Protein Serine-Threonine Kinases: metabolism (MeSH) ; Protein Serine-Threonine Kinases: genetics (MeSH) ; Signal Transduction (MeSH) ; Brain Neoplasms: pathology (MeSH) ; Brain Neoplasms: metabolism (MeSH) ; Myeloid Cells: metabolism (MeSH) ; Myeloid Cells: pathology (MeSH) ; Unfolded Protein Response (MeSH) ; Tumor Microenvironment (MeSH) ; Tumor Cells, Cultured (MeSH) ; Endoplasmic Reticulum Stress (MeSH) ; ER stress ; IRE1 ; chemokines ; glioblastoma ; inflammation ; Endoribonucleases ; Protein Serine-Threonine Kinases ; ERN1 protein, human

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Contributing Institute(s):

1. B050 Molekulare Genomanalyse (B050)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2024

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Essential Science Indicators ; IF >= 15 ; JCR ; Nationallizenz ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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