State-Selective Lethality & Glioblastoma Cellular Plasticity

How do anti-cancer therapies reshape glioblastoma cellular states? How can this plasticity be exploited therapeutically?

Using patient-derived glioma stem cells, single-cell RNA sequencing, CellTag lineage tracing, genetic perturbation and GLICO models, we characterize drug-induced transitions among major glioblastoma cellular states (Neftel et al., 2019). We found that different therapies can induce distinct and partially reversible state shifts, with HDAC inhibitor panobinostat promoting mesenchymal-like programs and PI3K inhibitor paxalisib promoting astrocyte-like programs.

By perturbing the mesenchymal-associated transcription factor FOSL1 and rationally combining drugs that drive opposing state transitions, we provide proof-of-concept evidence that targeting therapy-induced plasticity can enhance treatment response. This strategy, termed state-selective lethality, offers a framework for designing combinatorial therapies that overcome adaptive resistance in glioblastoma.

(Neftel et al., 2019)