Targeting Endoplasmic Reticulum proteostasis in cancer

Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Genetic and pharmacological evidence suggest that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept has been validated in triple negative breast cancer, prostate cancer as well as in glioblastoma multiform (GB), the most lethal primary brain cancer with an overall survival of 15 months and no effective treatment. We demonstrated that the ER stress sensor IRE1 contributes to GB progression, impacting tissue invasion and tumor vascularization. IRE1 is a dual Kinase/RNase that signals by catalyzing the non-conventional splicing of the mRNA encoding the transcription factor XBP1, and in addition by regulating RNA stability through a process known as Regulated IRE1 Dependent Decay (RIDD). We further investigated the contribution of IRE1 signaling to GB and defined a specific expression signature that when confronted to human GB transcriptomes showed the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor characteristics and outcomes. Moreover, using this signature we have explored the role of IRE1 signaling in tumor cells in reshaping the tumor microenvironment. These data identified IRE1 as an actionable therapeutic target which allowed us to use develop pharmacological approaches to enhance the efficacy of GB standard of care in mouse models.

PAVILLON 3 du bâtiment de la Surélévation