Glioblastoma invasion and cooption depend on IRE1α endoribonuclease activity

International audienceIRE1α 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 IRE1

High epiregulin expression in human U87 glioma cells relies on IRE1α and promotes autocrine growth through EGF receptor.

International audienceBACKGROUND: Epidermal growth factor (EGF) receptors contribute to the development of malignant glioma. Here we considered the possible implication of the EGFR ligand epiregulin (EREG) in glioma development in relation to the activity of the unfolded protein response (UPR) sensor IRE1α. We also examined EREG status in several glioblastoma cell lines and in malignant glioma. METHODS: Expression and biological properties of EREG were analyzed in human glioma cells in vitro and in human tumor xenografts with regard to the presence of ErbB proteins and to the blockade of IRE1α. Inactivation of IRE1α was achieved by using either the dominant-negative strategy or siRNA-mediated knockdown. RESULTS: EREG was secreted in high amounts by U87 cells, which also expressed its cognate EGF receptor (ErbB1). A stimulatory autocrine loop mediated by EREG was evidenced by the decrease in cell proliferation using specific blocking antibodies directed against either ErbB1 (cetuximab) or EREG itself. In comparison, anti-ErbB2 antibodies (trastuzumab) had no significant effect. Inhibition of IRE1α dramatically reduced EREG expression both in cell culture and in human xenograft tumor models. The high-expression rate of EREG in U87 cells was therefore linked to IRE1α, although being modestly affected by chemical inducers of the endoplasmic reticulum stress. In addition, IRE1-mediated production of EREG did not depend on IRE1 RNase domain, as neither the selective dominant-negative invalidation of the RNase activity (IRE1 kinase active) nor the siRNA-mediated knockdown of XBP1 had significant effect on EREG expression. Finally, chemical inhibition of c-Jun N-terminal kinases (JNK) using the SP600125 compound reduced the ability of cells to express EREG, demonstrating a link between the growth factor production and JNK activation under the dependence of IRE1α. CONCLUSION: EREG may contribute to glioma progression under the control of IRE1α, as exemplified here by the autocrine proliferation loop mediated in U87 cells by the growth factor through ErbB1

Le syndicalisme dans la France occupée

Émanant d’historien(ne)s du patronat, des salariés, des fonctionnaires et, fait plus singulier, de responsables de l’Institut d’histoire sociale et des instituts fédéraux de la CGT - qui ont favorisé l’accès à des archives inédites - les contributions rassemblées ici s’attachent surtout à l’analyse de pratiques syndicales multiples, surtout à l’échelle fédérale, dans la situation d’exception de guerre et d’occupation. Avec in fine un constat, corroborant celui formulé par Ian Kershaw à propos de l’Allemagne : « Les pressions économiques de la guerre » constituent sans doute un déterminant plus probant que les choix idéologiques. Du fait des archives disponibles - qui reflètent pour partie la pression des institutions vichyssoises - le volume privilégie, par nécessité, les fédérations de syndicats « légaux » : les ex-confédérés de la CGT - surtout les « fédéraux » loyaux au régime - ainsi que les syndicats patronaux, minorant de fait les autres échelles d’observation ainsi que les syndicats professionnels, la CFTC et les exunitaires de la CGT. Mais les acteurs de ce syndicalisme « légal » ne pouvant faire abstraction de celui qui l’est moins ou ne l’est pas du tout - sous des formes d’ailleurs complexes de cohabitation - le croisement des regards et des échelles a été poussé au plus loin pour analyser les épreuves exceptionnelles subies par les diverses formes du syndicalisme et, une fois refermée la parenthèse des années noires, les traces parfois durables qu’elles y ont laissées