Abstract 1253: Selectivity of regulated IRE1 dependent decay of RNA controls pro-oncogenic signaling in glioblastoma

Abstract

Abstract Glioblastoma multiforme (GBM) is the most lethal form of glioma with an overall survival at 5 years nearly null (< 5%). Increasing evidences point towards the RNase activity of IRE1 as a central player in GBM development, particularly in cancer cell invasion and tumor vascularization. Indeed, IRE1 promotes XBP1 mRNA splicing, a well-described cytoprotective transcription factor that is required for cancer cell survival. Moreover, regulated IRE1 dependent decay of RNA (RIDD) leads to opposite effects on cell fate depending the ER stress intensity or duration and on the target RIDD substrates. Recent studies unraveled the presence of somatic mutations on the IRE1 gene in GBM that could play a driver role but without providing any functional information. Here, we have sequenced IRE1 exons in 23 human GBMs and identified a new somatic mutation on the IRE1 gene. Interestingly, using biochemical approaches and an orthotopic tumor graft mouse model we show that this variant displays an altered RIDD selectivity in particular towards the specific RIDD substrates already characterized in GBM (SPARC and PER1) and also miR-17, a previously described RIDD substrate whose expression has also a prognostic value in GBM. IRE1-dependent gene expression pattern alterations lead to major functional consequences in terms of tumor phenotype including (i) a magnified induction of the inflammatory and pro-angiogenic pathways based on transcriptome signatures and (ii) an increase of the aggressiveness/infiltration potential of U87 derived tumors in mice. This study provides the first evidence that RIDD substrates selectivity can be modulated and unravels the first mechanistic example of how a somatic mutation in the IRE gene can provide adaptive advantages to glioblastoma cells. Note: This abstract was not presented at the meeting. Citation Format: Eric Chevet. Selectivity of regulated IRE1 dependent decay of RNA controls pro-oncogenic signaling in glioblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1253. doi:10.1158/1538-7445.AM2015-1253