Glioblastoma invasion and cooption depend on IRE1α endoribonuclease activity
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Arnaud Jabouille1,2, Maylis Delugin1,2, Raphaël Pineau2, Alexandre Dubrac3, Fabienne Soulet1,2, Stéphanie Lhomond2,4, Nestor Pallares-Lupon2,4, Hervé Prats3, Andreas Bikfalvi1,2, Eric Chevet2,4,5,6, Christian Touriol3, Michel Moenner1,2,7
1Inserm, U1029, 33400 Talence, France
2Univ. Bordeaux, 33000 Bordeaux, France
3Inserm, U1037, CHU de Rangueil, 31432 Toulouse, France
4Inserm, U1053, 33000 Bordeaux, France
5Centre Régional de Lutte Contre le Cancer Eugène Marquis, 35000 Rennes, France
6ER440, « Oncogenesis, stress, signaling » Univ. Rennes 1, Rennes, France
7CNRS UMR5095, IBGC, 33700 Bordeaux, France
Michel Moenner, e-mail: firstname.lastname@example.org
Arnaud Jabouille, e-mail: email@example.com
Keywords: Pathology Section, glioblastoma, angiogenesis, invasion, perivascular growth, mesenchymal differentiation
Received: June 24, 2015 Accepted: July 10, 2015 Published: July 23, 2015
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.
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