ANGI-01. TRANSFORMATION OF TUMOR ENDOTHELIAL CELLS TO MESENCHYMAL STEM CELL-LIKE CELLS INDUCES THERAPY RESISTANCE IN GLIOBLASTOMA

Abstract

Newly formed tumor blood vessels deliver oxygen and nutrients and produce paracrine factors to tumor microenvironment, fueling tumor growth, progression and metastasis. Likewise, targeting vascular endothelial cells (ECs) has emerged as a fundamental strategy for cancer treatment. However, inefficient eradication and insufficient functional inhibition of tumor-associated ECs remains a major barrier for current anti-vascular therapies. As such, current anti-angiogenic therapies that mainly target vascular endothelial growth factor (VEGF) have encountered difficulties and failure in most types of malignant cancers. Our recent work has identified endothelial mesenchymal transformation in glioblastoma (GBM), which leads to the suppression of VEGF signaling in GBM-associated ECs and renders intrinsic EC resistance to anti-VEGF treatment (Huang et al, JCI 2016). Here, we reveal cell plasticity in ECs drives their resistance to chemotherapy. Our data show that tumor ECs derived from human GBM patients are resistant to chemotherapy, and the resistance correlates with the mesenchymalization in ECs. Utilizing EC lineage tracing in a genetic murine GBM model, we show that mesenchymal transformation induces EC resistance to temozolomide (TMZ) chemotherapy. Interestingly, transcriptome analysis by RNA deep sequencing reveals that ECs undergo transformation to mesenchymal stem cell (MSC)-like cells after expose to GBM microenvironment. ECs acquire MSC signature genes and stemness-associated transcriptional activation, leading to chemoresistance. Our further mechanistic study identifies a c-Met-mediated axis that induces canonical activation of Wnt signaling. Finally, genetic ablation and pharmacological inhibition of c-Met reduce EC transformation and overcome chemoresistance in ECs. These findings illustrate a cell transformation-based mechanism that controls chemoresistance in tumor ECs, and suggest that targeting c-Met may sensitize ECs to chemotherapy and improve anti-vascular treatment for cancers.