CS-31 * A NOVEL YAP-DRIVEN MIGRATION AND INVASION SIGNALING PATHWAY PREDICTS POOR OUTCOME IN GLIOBLASTOMA

One of the hallmarks of tumor malignancy is the ability of cells to not only locally invade its surrounding parenchyma but also distally metastasize. Aggressive tumors such as glioblastoma (GBM) often display a collective sheet of migrating cells which may eventually disseminate and migrate in a single cell manner. By integrating extracellular cues and intracellular signaling, cell polarization and the persistence and speed of locomotion is tightly governed. Given the diverse inputs that may modulate this intricate cell migration pathway, it is of interest to identify critical modulators of this network. Yes-associated protein (YAP), a transcriptional regulator, has been suggested to potentiate migration, invasion, and metastasis; however, it is not known how or whether YAP expression and activity can regulate the molecular networks controlling cell migration and invasion, and whether this function of YAP may be consequential to the progression of aggressive cancers. We thus explored mechanisms of YAP-mediated migration and invasion in normal cells as well as cancer cells where YAP is hyperactive (p < 0.05). We found that YAP plays a pivotal role in regulation of this complex migratory and invasive behavior through a novel small Rho-GTPase-dependent signaling mechanism. As with GBM, metastatic cancers often evade detection because individual cells spread from the primary bulk tumor; thus, making complete resection and treatment virtually impossible. Congruent with our in vitro studies, our murine intracranial xenograft model argue the role of YAP in driving invasive tumor growth (p < 0.05). Moreover, we demonstrate that these YAP-driven cell dispersal mechanisms confer poor patient prognosis in the TCGA and REMBRANDT GBM databases (p < 0.05). Thus, our findings provide new insights into the biology of aggressive cancers with particular prognostic relevance of this YAP-driven pro-motility cascade in glioblastoma. In addition, our studies suggest these YAP-dependent mechanisms are evolutionary conserved during development and regeneration and co-opted by pathological diseases.