217 YAP Is Ready to Rac and Rho: Elucidation of a Novel YAP-Driven Network That Potentiates Brain Cancer Cell Dispersal and Confers Poor Survival in Patients

• Published in: Neurosurgery Vol. 63; no. CN_suppl_1; p. 185
• Main Authors: Shah, Sagar R., Tippens, Nathaniel, Park, JinSeok, Mohyeldin, Ahmed, Vela, Guillermo, Martinez-Gutierrez, Juan Carlos, Margolis, Seth S, Schmidt, Susanne, Levchenko, Andre, Quinones-Hinojosa, Alfredo
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01-08-2016; Copyright by the Congress of Neurological Surgeons; Wolters Kluwer Health, Inc
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - mortality; Cell adhesion & migration; Gene Expression Profiling; Gene Regulatory Networks - genetics; Gene Regulatory Networks - physiology; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - mortality; Humans; Medical prognosis; Neurosurgery; Phosphoproteins - genetics; Phosphoproteins - metabolism; rac GTP-Binding Proteins - genetics; rac GTP-Binding Proteins - metabolism; rho GTP-Binding Proteins - genetics; rho GTP-Binding Proteins - metabolism; Transcriptome - genetics; Transcriptome - physiology
• ISSN: 0148-396X; 1524-4040
• DOI: 10.1227/01.neu.0000489786.22041.2d

Abstract
INTRODUCTION:
Molecular pathways linking cell polarization and migration to extracellular cues regulate many pathological processes, including progression of aggressive and infiltrative cancers. Glioblastoma (GBM), the most common and lethal form of primary brain cancer, is characterized by its pronounced ability to disseminate into the intricate microenvironment of the human brain, confounding surgical excision and radiotherapy, leading to a median patient survival of 14 months. Progression results from defects in molecular pathways linking cell migration and invasion into surrounding tissue. However, the molecular engines are not known.
METHODS:
Using patient-derived GBM tissues and cells, we profiled the expression of network moieties via Western blotting, quantitative real-time polymerase chain reaction and performed live cell time-lapse microscopy, bioinformatics analyses, in vivo intracranial GBM experiments using genetic and pharmacological inhibitors to delineate a prodispersal mechanism for management and treatment of GBMs.
RESULTS:
Yes-associated protein (YAP), a transcriptional coactivator, is overexpressed and hyperactive in 78% of GBMs and 50% of metastatic tumors to the brain (P < .05). Our studies demonstrate that YAP activates a Rho-GTPase switch to potentiate migratory speed by interacting with canonical pathways through direct transcriptional control. In addition, YAP mediates a proinvasive genetic network by direct posttranslational regulation. By coupling the regulation of migration and invasion, YAP drives tumor cell dispersal in vitro and in vivo (P < .05). Hyperactivation of this YAP-driven network in GBM confers poor patient outcome in clinical biopsies and The Cancer Genome Atlas (P < .05), suggesting a new signature in clinical prognosis of this aggressive and infiltrative cancer. Targeting this network using a proprietary pharmacological inhibitor attenuates tumor dispersal and growth (P < .05).
CONCLUSION:
YAP can critically control cellular locomotion through direct interaction with canonical molecular pathways controlling invasion and migration. Understanding the molecular underpinnings of this network is vital to the development of imperative prognostic and treatment approaches for cancer such as the new proprietary pharmacological inhibitor presented in this study.