Abstract PR011: Targeting cellular plasticity-driven metabolic adaptation to overcome chemoresistance in GBM

Glioblastoma is an incredibly aggressive primary brain tumor that is universally lethal due to 100% recurrence. Recent research has pointed to the existence of a population of cells that possess stem cell-like characteristics that are resistant to conventional therapy and can initiate recurrence. Our laboratory, along with others, has demonstrated that this stem-like state is plastic and can be acquired by otherwise differentiated GBM cells exposed to different stress, including stress generated by chemotherapy. Our Initial investigation indicated that Polycomb group protein EZH2 is critical for therapeutic stress-induced cellular plasticity. Further investigation revealed that the mechanisms of EZH2-mediated cellular plasticity are partly governed by a novel downstream target ARL13B, a member of the ADP-ribosylation factor-like family protein critical for cilia formation and maintenance. ARl13B removal significantly reduced different stemness factors such as nestin, SOX2, and most importantly, sensitized different subtypes of patient-derived xenograft lines to temozolomide-based chemotherapy both in vitro and in vivo (p