Radiation-reprogrammed glioma stem cells generate vascular-like cells to build a trophic niche driving tumor recurrence

Abstract

Radiation-resistant glioma cells exhibit phenotypic plasticity leading to aggressive tumor recurrence. However, the underlying molecular mechanisms remain to be elucidated. Here, we employed single-cell and whole transcriptomic analyses to discover that radiation induces a dynamic shift in proportions and functional states of glioma cells allowing for acquisition of vascular- and mesenchymal-like phenotypes. The primary phenotypic switch induced by radiation is transdifferentiation to endothelial-like and pericyte-like cells. In turn, the transdifferentiated cells promote proliferation of radiated tumor cells, and their selective depletion results in reduced tumor growth post-treatment. The acquisition of vascular-like phenotype is driven by increased chromatin accessibility in vascular genes, and blocking P300-mediated histone acetyltransferase activity prior to radiation inhibits vascular transdifferentiation and tumor growth. Our findings indicate that radiation reprograms glioma cells driving vascular transdifferentiation and tumor recurrence, and highlights P300 HAT inhibitor as a potential therapeutic target for preventing GBM relapse.