Tami-30. therapy induced reprogramming drives glioma vascular transdifferentiation and tumor recurrence

Abstract Therapy-resistant glioma cells elicit phenotypic plasticity leading to aggressive tumor recurrence. Here, we employed single-cell and whole transcriptomic analyses to uncover that a standard glioma treatment, radiation induces a dynamic shift in functional states of glioma cells allowing for acquisition of mesenchymal-like and vascular-like phenotypes. The predominant phenotype switch induced by radiation in surviving tumor cells is transdifferentiation to endothelial-like and pericyte-like cells. The transdifferentiated cells in turn promote proliferation of radiated tumor cells, and their selective depletion results in reduced tumor growth and recurrence 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 treatment inhibits vascular transdifferentiation and tumor growth. Our findings indicate that radiation therapy reprograms tumor cells driving vascular transdifferentiation, and highlights HAT inhibitors as potential therapeutic target for preventing GBM relapse