Deciphering mechanisms of perivascular tumor cell invasion in glioblastoma

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DESCRIPTION (provided by applicant): Glioblastoma multiformes (GBMs) are primary brain tumors displaying invasive growth properties that are tightly coupled to the vasculature. For example, stem-like GBM cells preferentially cluster in perivascular niches and invasive GBM cells often disperse throughout the brain via vascular basement membranes. Furthermore, anti-angiogenesis therapies administered to patients with GBM often lead to enhanced tumor cell infiltration and the formation of lethal satellite lesions. The molecular mechanisms that couple GBM cells to cerebral blood vessels during tumor progression and following anti-angiogenesis therapies remain largely unknown. In this project we will investigate how GBM cells exploit a specific cell adhesion and signaling axis comprised of ?v?8 integrin, its latent TGF? extracellular matrix (ECM) protein ligands, and TGF? receptors to selectively promote perivascular growth and dispersal in the brain. We have discovered that ?v?8 integrin is expressed in invasive GBM cells where it mediates activation of TGF?s to drive cell polarity and directional migration. In addition, ?v?8 integrin protein is highly expressed in invasive GBM cells following anti-angiogenesis treatments. Based on these data we hypothesize that ?v?8 integrin regulates adhesion and signaling pathways that promote GBM cell invasion during tumor progression and following anti-vascular therapies. Furthermore, we hypothesize that inhibiting components of these pathways will diminish GBM cell infiltration. To test our hypotheses we have developed a unique set of experimental tools to (1) characterize how ?v?8 integrin interacts with the VEGF-A receptor Neuropilin-1 to promote GBM cell infiltration; (2) investigate how integrin-activated TGF?s cooperate with VEGF-A to drive GBM cell invasiveness; and (3) selectively inhibit components of these pathways to block invasiveness in pre-clinical mouse models of GBM. Collectively, these experiments will not only elucidate novel links between ?v?8 integrin-activated TGF?s and VEGF-A receptors in GBM cells, but may eventually lead to new therapeutic strategies for inhibiting cell invasion during tumor progression and following anti-vascular therapies.