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, qRT-PCR and performed live cell time-lapse microscopy, bioinformatics analyses, in vivo intracranial GBM experiments using genetic and pharmacological inhibitors to delineate a pro-dispersal mechanism for management and treatment of GBMs.
Results: Yes-associated protein (YAP), a transcriptional co-activator, is overexpressed and hyperactive in 78% of GBMs and 50% of metastatic tumors to the brain (p<0.05). 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 pro-invasive genetic network by direct post-translational regulation. By coupling the regulation of migration and invasion, YAP drives tumor cell dispersal in vitro and in vivo (p<0.05). Hyperactivation of this YAP-driven network in GBM confers poor patient outcome in clinical biopsies and TCGA (p<0.05), 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<0.05).
Conclusions: 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.
Patient Care: Our studies unravel a conserved signaling mechanism driving migratory and invasive capacity of GBM cells. This YAP-driven network has significant prognostic power. Moreover, targeting this network using novel FDA-approved therapies attenuates aggressive behavior -- hence offering a new target and potential drug for treatment after further appropriate evaluation.
Learning Objectives: "By the conclusion of this session, participants should be able to: 1) Describe the importance of identifying and delineating aggressive genetic networks in cancer 2) Understand the role of YAP and its direct modulation of canonical pathways controlling of migratory and invasive capacity of GBMs 3)Understand prognostic and therapeutic power of these network studies 4)Appreciate the use of novel-FDA approved drugs in targeting aggressive genetic networks