TMIC-11NOVEL ANGIOCRINE CANDIDATES IN GLIOBLASTOMA PROGENITOR CELL PERIVASCULAR NICHE INTERACTIONS

Abstract

Glioblastoma (GBM) cells promote and rely on tumor-associated vessels that form a structurally and functionally aberrant microvascular environment contributing to pathology, malignancy, and clinical prognosis. Self-renewing and multipotential tumor progenitor cells (TPCs) reside in close association with this microvasculature, which maintains them in a stem-like state. However, the factors responsible for this maintenance are still unknown. Given their contribution to normal vasculature, we examined the role of tumor associated endothelial cells (ECs) on GBM progression. We found that patient-derived gliomaspheres grown in 50% conditioned media, from GBM ECs, exhibited increased sphere initiating potential. Adopting an unbiased top-down experimental approach utilizing RNA-sequencing technology, we thus generated an angiocrine driven interactome of the entire set of secreted or cell surface molecules expressed in GBM associated ECs and TPCs, from the same primary GBMs, to elucidate the factors and signaling pathways underlying TPC dependence on its perivascular niche. We have identified prominent angiocrine candidates including members of the Small Integrin-Binding Ligand N-linked Glycoprotein (SIBLING) and Wnt family of proteins secreted by ECs, interacting with integrin and Frizzled binding partners on TPCs, respectively. SIBLING angiocrines integrin-binding sialoprotein (IBSP), dentin sialophosphoprotein (DSPP), and Osteopontin (OPN) may have key roles in multiple stages of cancer development and expansion. Unequivocal roles for OPN in tumor propagation has been previously reported, thus validating our methodology. IBSP and DSPP represent novel GBM perivascular niche signaling angiocrines with possibly redundant and/or combinatorial roles with OPN. Their potential binding partners, ITGA4, 5, and ITGB1, with roles in MMP localization, tumor motility and progression, and CD44, with possible role in TPC self-renewal, are all upregulated in our GBM TPCs. Targeting such angiogrines may allow for inhibition of GBM progression and may elucidate mechanisms of GBM recurrence as tumor cells spread into the parenchyma, necessitating, uncoupling TPC survival and the vascular niche.