Glioblastoma invasion and cooption depend on IRE1α endoribonuclease activity

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.

Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer

“…Interestingly, glioma cells adapt to loss of IRE1α-mediated angiogenesis by enhancing mesenchymal differentiation and invasiveness to facilitate growth along established blood vessels, suggesting IRE1α may exert tumor type-specific angiogenic functions. The IRE1α kinase domain, but not the endoribonuclease domain, inhibited this vessel co-option, suggesting that vascularization can proceed independently of XBP1 or RIDD in certain cancer types (Jabouille et al, 2015). Thus, IRE1α can therefore promote new vessel formation at the expense of other vascularization modes, though whether this occurs in other cancer types remains to be determined.…”

Endoplasmic reticulum proteostasis in glioblastoma—From molecular mechanisms to therapeutic perspectives

“…A connection between IRE1, PERK, and angiogenesis is observed in several tumor cell types, including breast and brain cancers as well as head and neck squamous and lung carcinomas (43,55). In GBM, IRE1 appears as a major regulator of invasion and angiogenesis (71). IRE1 RNase activity targets the mRNA of SPARC, a secreted matricellular protein that regulates the interaction between GBM cells and extracellular matrix, promoting GBM cell migration (72).…”

Signaling the Unfolded Protein Response in primary brain cancers

“…There is strong evidence towards a major involvement of UPR signaling in GBM oncogenesis and resistance to treatments. As such, work from our group has clearly established the contribution of IRE1α signaling in GBM and particularly in tumor growth ((Auf et al, 2013), neo-angiogenesis (Auf et al, 2010b;Drogat et al, 2007;Pluquet et al, 2013b) and migration/invasion properties (Dejeans et al, 2012;Jabouille et al, 2015)). Moreover, the PERK pathway has also been involved in the control of GBM cells metabolism (Hou et al, 2015) and response to treatment Yacoub et al, 2010).…”