Abstract

Abstract Glioblastoma (GB) is one of the deadliest types of human cancer. Despite a very aggressive treatment regime-including resection, chemo-radiation, its recurrence rate is more than 90%. Recurrence is mostly caused by highly resistant and invasive cells that spread from tumor bulk and are not removed by resection. To develop an effective therapeutic approach, we need to better understand underlying molecular and cellular mechanism driving therapy resistance and invasion in GB. To dynamically track the changes post-therapy and chemoradiation-resistant cells, we employed multiple bulk and single cell transcriptomics, phosphoproteome, in vitro and in vivo real time imaging, organotypic cultures, functional analysis, digital pathology and spatial transcriptomics on patient material and preclinical models of GB. We demonstrated that the chemoradiation and brain vasculature induce a transition to invasive functional cell state, which we rename as VC-Resist. Better cell survival, G2M arrest, senescence/stemness pathway induction, makes this GB state much more resistant. Notably, these GB cells are highly vessel co-opting allowing homing to perivascular niche, which in turn increases their transition to this cell state. Molecularly, the transition to VC-Resist cell state takes place through FGF-FGFR1 signaling that leads to activation of DNA damage repair, YAP and Rho pathways. These findings demonstrate that the perivascular niche and GB cell plasticity jointly generates a vicious loop that leads to resistance and brain infiltration during GB recurrence.