Angi-10. Chemotherapeutic Stress Induces Transdifferentiation of Glioblastoma Cells to Promote Vascular Mimicry

Abstract

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor affecting adults, with a median survival of approximately 21 months after diagnosis. A key factor underlying the limited efficacy of current treatment modalities is the remarkable plasticity exhibited by GBM cells, which allows them to effectively adapt to changes induced by our current treatment strategies. In addition to their plasticity, GBM tumors are also highly vascularized with aberrant vessels that further promote its aggressiveness. Recent research has demonstrated that GBM cells have the ability to transdifferentiate into endothelial cells (ECs), which suggests that GBM cells may use their properties of plasticity and vascularity in concert, leading to the creation of tumor-derived blood vessels. The mechanism behind this transdifferentiation remains unclear. Here, we show that treatment with temozolamide (TMZ)-based chemotherapy (the current standard of care) induces time-dependent increases in expression of markers for glioma stem cells (GSCs) and immature and mature ECs over 8 days of treatment (p < .001) in multiple patient-derived xenograft (PDX) lines. In addition, GBM tumors growing as orthotopic xenografts in nude mice showed significantly increased expression of GSC markers (CD15 and CD133) and EC markers (CD105 and CD144) after 8 days of TMZ treatment (p < .01). Ex-vivo FACS analysis of these orthotopic xenografts showed the presence of immature and mature EC populations in addition to GSC populations. To assess the functionality of these increased EC populations, a tube forming assay was performed. Results showed that the tube forming capacity of PDX lines was significantly increased (p < .01) after therapy. Furthermore, immunofluorescence analysis revealed increased tumor-derived vessels in TMZ-recurrent tumors. Overall, this study identifies chemotherapeutic stress as a new driver of transdifferentiation of tumor cells to endothelial cells and highlights cellular plasticity as a key player in therapeutic resistance and tumor recurrence.