STMC-32. THE MESENCHYMAL SUBTYPE OF GLIOMA STEM-LIKE CELLS EXHIBITS REDUCED ENDOPLASMIC RETICULUM STRESS

Abstract

GBM is a lethal brain tumor that contains two major cancer stem cell subtypes (Proneural, PN and Mesenchymal, MES) bestowed with tumor initiating properties. Of these two subtypes, the MES glioma stem-like cells (GSCs) are associated with increased radioresistance, and thus it is important to identify essential molecules that regulate their survival and proliferation. Here, we performed 2D gel proteomic comparison of PN versus MES tumors and discovered higher expression of the endoplasmic chaperone protein GRP78 in the MES subtype of GBMs. In addition, TCGA analyses showed significantly higher expression of GRP78 and SOD2 in the MES GBM subtype compared to all other subtypes of GBM (Proneural, Classical, Neural). MES GSCs contained lower baseline levels of the unfolded protein response (UPR) and reactive oxygen species (ROS), verifying our hypotheses that MES GSCs exhibit reduced ER stress. Consistently, MES GSCs showed more resistance to low-glucose and tunicamycin-stimulation both of which induce the ER stress and oxidative stress. Intriguingly, lesser ER stress translates to increased protein synthesis and as consequence we found MES GSCs show increase protein synthesis and larger cell size. Currently we are exploring strategies to knockout GRP78 and study its impact on MES GSC self-renewal, proliferation and tumorigenesis.