Endothelial plasticity in glioma vascularization and therapy resistance

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Project Summary Glioblastoma (GBM), the grade IV glioma, is among the most lethal of human malignancies, distinguished by prominent vascularity. GBM is the most aggressive primary brain tumor with a current median survival of about 14-16 months, largely due to its high resistance to conventional cytotoxic therapies. Overgrown vasculature characterizes the tumor microenvironment that fuels GBM progression and induces vascular niche-mediated therapeutic resistance. However, current anti-vascular therapy that primarily targets pro- angiogenic factors including VEGF, albeit initially groundbreaking, has encountered major difficulties and failures in treating most malignant solid tumors including GBM, likely due to insufficient eradication or functional inhibition of tumor-associated endothelial cells (ECs). Our recent studies suggest that EC plasticity by genetic reprogramming is a driving force that induces EC resistance to anti-angiogenic and cytotoxic treatments. Here, our preliminary study by single-cell transcriptome analysis of tumor-associated ECs reveals that ECs acquire mesenchymal and stemness-like gene signature in a genetically engineered mouse GBM model. Utilizing human specimens and EC lineage-tracing systems, our studies reveal robust treatment resistance in GBM-associated ECs. Our in vitro and in vivo data suggest that genetic reprogramming into mesenchymal stem cell (MSC)-like cells induces EC chemoresistance through Wnt activation in GBM. Therefore, we hypothesize that mesenchymal and stemness-like genetic reprogramming in tumor ECs induces therapy resistance in GBM. We will test this hypothesis by pursuing the following aims: 1) Define the molecular mechanism underlying EC plasticity and treatment resistance with a focus on Wnt activation; 2) Determine the in vivo role of c-Met/Wnt-mediated EC plasticity in tumor progression; and 3) Test experimental therapy that combines EC plasticity inhibition with radio/chemotherapy or anti-angiogenic therapy in orthotopic mouse GBM models. Successful completion of the proposed work will provide novel insights into tumor microenvironment-dependent treatment resistance, and may lead to development of a new therapeutic strategy by targeting endothelial plasticity in cancer.