Glioblastoma vessel co-option occurs as a resistance mechanism to chemoradiation via induction of a persister cell state

Glioblastoma (GB) is one of the deadliest types of human cancer. Recurrence after chemoradiation is mostly caused by regrowth of highly invasive and resistant cells. There is an urgent need to better understand the underlying GB mechanisms of chemoradiation resistance and tumor spreading. Using a combination of transcriptomic analysis, longitudinal imaging, organotypic cultures, functional assays, animal studies and clinical data analyses, we demonstrated that chemoradiation and brain vasculature induce a transition to an invasive functional cell state that we named VC-Resist. Better cell survival, G2M-arrest, senescence/stemness pathways’ induction and YAP activation make this GB cell state more resistant to therapy. Notably, these persister GB cells are highly vessel co-opting, allowing homing to the perivascular niche, which in turn increases their transition to this cell state. These findings demonstrate how vessel co-option, the perivascular niche, and GB cell plasticity jointly drive resistance during GB recurrence. Gene expression profiling analysis of RNA-seq data for MGG4, MGG18, GL261 GBM cells based on a cells state reporter expression (Nestin reporter, high or low expression of the reporter). Profiling of MGG4 after therapies in vitro and in-vivo (TMZ-temozolomide or IR-irradiation). Profiling of MGG4 after culture with brain blood vessels (BV) and corresponding controls without blood vessels (BV-CTL).