Autocrine control of glioma cells adhesion and migration through IRE1α-mediated cleavage of SPARC mRNA

The endoplasmic reticulum (ER) is an organelle specialized for the folding and assembly of secretory and transmembrane proteins. ER homeostasis is often perturbed in tumor cells because of dramatic changes in the microenvironment of solid tumors, thereby leading to the activation of an adaptive mechanism named the unfolded protein response (UPR). The activation of the UPR sensor IRE1 alpha has been described to play an important role in tumor progression. However, the molecular events associated with this phenotype remain poorly characterized. In the present study, we examined the effects of IRE1 alpha signaling on the adaptation of glioma cells to their microenvironment. We show that the characteristics of U87 cell migration are modified under conditions where IRE1 alpha activity is impaired (DN_IRE1). This is linked to increased stress fiber formation and enhanced RhoA activity. Gene expression profiling also revealed that loss of functional IRE1 alpha signaling mostly resulted in the upregulation of genes encoding extracellular matrix proteins. Among these genes, Sparc, whose mRNA is a direct target of IRE1 alpha endoribonuclease activity, was in part responsible for the phenotypic changes associated with IRE1 alpha inactivation. Hence, our data demonstrate that IRE1 alpha is a key regulator of SPARC expression in vitro in a glioma model. Our results also further support the crucial contribution of IRE1 alpha to tumor growth, infiltration and invasion and extend the paradigm of secretome control in tumor microenvironment conditioning.