Phenotype stability under dynamic brain-tumor environment stimuli maps glioblastoma progression in patients

Although tumor invasiveness is known to drive glioblastoma (GBM) recurrence, current approaches to treatment assume a fairly simple GBM phenotype transition map. We provide new analyses to estimate the likelihood of reaching or remaining in a phenotype under dynamic, physiologically likely perturbations of stimuli (“phenotype stability”). We show that higher stability values of the motile phenotype (Go) are associated with reduced patient survival. Moreover, induced motile states are capable of driving GBM recurrence. We found that the Dormancy and Go phenotypes are equally represented in advanced GBM samples, with natural transitioning between the two. Furthermore, Go and Grow phenotype transitions are mostly driven by tumor-brain stimuli. These are difficult to regulate directly, but could be modulated by reprogramming tumor-associated cell types. Our framework provides a foundation for designing targeted perturbations of the tumor-brain environment, by assessing their impact on GBM phenotypic plasticity, and is corroborated by analyses of patient data.