Glioblastoma invasion and cooption depend on IRE1α endoribonuclease activity.
IRE1α is an endoplasmic reticulum (ER)-resident transmembrane signaling protein and a cellular stress sensor. The protein harbors a cytosolic dual kinase/endoribonuclease activity required for adaptive responses to micro-environmental changes. In an orthotopic xenograft model of human glioma, invalidation of IRE1α RNase or/and kinase activities generated tumors with remarkably distinct phenotypes. Contrasting with the extensive angiogenesis observed in tumors derived from control cells, the double kinase/RNase invalidation reprogrammed mesenchymal differentiation of cancer cells and produced avascular and infiltrative glioblastomas with blood vessel co-option. In comparison, selective invalidation of IRE1α RNase did not compromise tumor angiogenesis but still elicited invasive features and vessel co-option. In vitro, IRE1α RNase deficient cells were also endowed with a higher ability to migrate. Constitutive activation of both enzymes led to wild-type-like lesions. The presence of IRE1α, but not its RNase activity, is therefore required for glioblastoma neovascularization, whereas invasion results only from RNase inhibition. In this model, two key mechanisms of tumor progression and cancer cell survival are functionally linked to IRE1α.
Inserm, U1029, 33400 Talence, France.|Université de Bordeaux, 33000 Bordeaux, France.
Arnaud
A
Jabouille
Inserm, U1029, 33400 Talence, France.|Université de Bordeaux, 33000 Bordeaux, France.
Maylis
M
Delugin
Université de Bordeaux, 33000 Bordeaux, France.
Raphaël
R
Pineau
Inserm, U1037, CHU de Rangueil, 31432 Toulouse, France.
Alexandre
A
Dubrac
Inserm, U1029, 33400 Talence, France.|Université de Bordeaux, 33000 Bordeaux, France.
Fabienne
F
Soulet
Université de Bordeaux, 33000 Bordeaux, France.|Inserm, U1053, 33000 Bordeaux, France.
Stéphanie
S
Lhomond
Université de Bordeaux, 33000 Bordeaux, France.|Inserm, U1053, 33000 Bordeaux, France.
Nestor
N
Pallares-Lupon
Inserm, U1037, CHU de Rangueil, 31432 Toulouse, France.
Hervé
H
Prats
Inserm, U1029, 33400 Talence, France.|Université de Bordeaux, 33000 Bordeaux, France.
Andreas
A
Bikfalvi
Université de Bordeaux, 33000 Bordeaux, France.|Inserm, U1053, 33000 Bordeaux, France.|Centre Régional de Lutte Contre le Cancer Eugène Marquis, 35000 Rennes, France.|ER440, Oncogenesis, Stress, Signaling, Université Rennes 1, Rennes, France.
Eric
E
Chevet
Inserm, U1037, CHU de Rangueil, 31432 Toulouse, France.
Christian
C
Touriol
Inserm, U1029, 33400 Talence, France.|Université de Bordeaux, 33000 Bordeaux, France.|CNRS UMR5095, IBGC, 33700 Bordeaux, France.
Michel
M
Moenner
D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy / Q000201:enzymology*; D006801:Humans; D015151:Immunoblotting; D053208:Kaplan-Meier Estimate; D051379:Mice; D018613:Microscopy, Confocal; D009154:Mutation; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D004318:Doxycycline
Pathology Section; angiogenesis; glioblastoma; invasion; mesenchymal differentiation; perivascular growth