Oncotarget

Research Papers:

Glioblastoma invasion and cooption depend on IRE1α endoribonuclease activity

Arnaud Jabouille _, Maylis Delugin, Raphaël Pineau, Alexandre Dubrac, Fabienne Soulet, Stéphanie Lhomond, Nestor Pallares-Lupon, Hervé Prats, Andreas Bikfalvi, Eric Chevet, Christian Touriol, Michel Moenner

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Oncotarget. 2015; 6:24922-24934. doi: 10.18632/oncotarget.4679

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Abstract

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

Correspondence to:

Michel Moenner, e-mail: michel.moenner@u-bordeaux.fr

Arnaud Jabouille, e-mail: arnaud.jabouille@ucsf.edu

Keywords: Pathology Section, glioblastoma, angiogenesis, invasion, perivascular growth, mesenchymal differentiation

Received: June 24, 2015     Accepted: July 10, 2015     Published: July 23, 2015

ABSTRACT

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.

Author Information

Arnaud Jabouille
Primary Contact  _

Maylis Delugin

Raphaël Pineau

Alexandre Dubrac

Fabienne Soulet

Stéphanie Lhomond

Nestor Pallares-Lupon

Hervé Prats

Andreas Bikfalvi

Eric Chevet

Christian Touriol

Michel Moenner


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