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Oncotarget. 2015 Sep 22;6(28):24922-34. doi: 10.18632/oncotarget.4679.

Glioblastoma invasion and cooption depend on IRE1α endoribonuclease activity.

Author information

1
Inserm, U1029, 33400 Talence, France.
2
Université de Bordeaux, 33000 Bordeaux, France.
3
Inserm, U1037, CHU de Rangueil, 31432 Toulouse, France.
4
Inserm, U1053, 33000 Bordeaux, France.
5
Centre Régional de Lutte Contre le Cancer Eugène Marquis, 35000 Rennes, France.
6
ER440, Oncogenesis, Stress, Signaling, Université Rennes 1, Rennes, France.
7
CNRS UMR5095, IBGC, 33700 Bordeaux, France.

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.

KEYWORDS:

Pathology Section; angiogenesis; glioblastoma; invasion; mesenchymal differentiation; perivascular growth

PMID:
26325176
PMCID:
PMC4694804
DOI:
10.18632/oncotarget.4679
[Indexed for MEDLINE]
Free PMC Article
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