Targeting Glioblastoma Cell State Plasticity for Enhanced Therapeutic Efficacy

Summary Glioblastoma (GBM) is the most common and deadly primary brain cancer, with limited therapeutic options. Treatment failure has been associated with intratumoral heterogeneity and the acquisition of a pronounced mesenchymal-like (MES-L) phenotype after recurrence. Here, we have screened a panel of drugs with diverse mechanisms of action across two patient-derived glioblastoma stem cells (GSCs) to characterize the dynamics of drug-mediated transcriptomic cellular state changes. Our results demonstrate that anti-tumor drugs induce significant but reversible alterations in cellular state distribution at the single-cell level in a drug-specific manner, influencing transitions between mesenchymal and the neurodevelopmental astrocytic-like (AC-L) states. Utilizing barcoded analysis in our recently developed ex vivo glioblastoma cerebral organoid (GLICO) model, we discerned distinct cell state sensitivities to the MES-L enhancing histone deacetylase inhibitor, panobinostat, which are contingent on the inducible modulation of the mesenchymal transcription factor FOSL1. The strategic combination of MES-L enhancing and MES-l suppressing genetic perturbations or drugs significantly increases anti-glioma activity in a strategy we call state-selective lethality. Overall, our findings highlight the critical role of cell state plasticity in the response of GSCs to anti-tumor therapeutic stress and underscore the potential for novel GBM combination drug strategies.