TMIC-36. CROSSTALK OF GLIOMA STEM CELLS WITH VASCULAR ENDOTHELIAL CELLS PERSISTS THEIR PRONEURAL PHENOTYPE AND THERAPY RESISTANCE VIA ENDOCAN-CD11A INTERACTION

Abstract

GBM cells tend to invade into adjacent normal brain tissues and cannot be completely resected surgically. These remaining tumor cells are the "seeds" to escape post-surgical therapies, hence contributing to tumor recurrence. The exact mechanisms by which these seeds confer to therapy resistance remains elusive. Several studies have shown the functional contribution of tumor microenvironment to glioma stemness and highlighted the importance of vascular endothelial(VE) cells in tumor initiation and progression. Here, we aim to determine the role of crosstalk of VE cells with glioma stem cells (GSCs) to develop GBM recurrence. We first assessed the effect of VE conditioned media (VE-CM) on patient-derived GBM neurospheres in vitro and in vivo. Culturing GBM neurospheres with VE-CM or their coculturing with VE cells promoted growth and migration of GBM neurospheres. Mice coinjected with VE cells and GBM neurospheres resulted in an increase of tumor growth compared to the injection of GBM neurospheres alone. To understand the mechanism of action, we performed RNA sequencing with CD31+ VE cells and A2B5+ GSCs directly isolated from patients with therapy-refractory epilepsy or GBM to identify factors secreted by these cells. We identified that Endocan is upregulated in VE cells, whereas CD11a – a receptor for Endocan, is upregulated in GSCs. Preferential expression of CD11a in perivascular region of GBM tissues was observed by immunohistochemistry. Irradiating VE cells substantially increased ESM1, by which VE cells provide extrinsic signals for elevated malignancy of GSCs after radiation therapy. Functionally, adding VE-CM or recombinant ESM1 protected GBM neurospheres from undergoing irradiation induced apoptosis and mesenchymal transition. We are currently investigating exact mechanism by which Endocan secretion from VE cells promotes GSC malignancy after radiation. Taking these data together, targeting ESM1 in VE cells or CD11a in GBM cells may provide a novel and effective strategy for preventing GBM recurrence.