Gliomas are the most aggressive and least successfully treated brain tumors because of their distinctive ability to infiltrate surrounding brain tissue. Even if the bulk of the tumor is removed, migratory cells left behind are not detected by the immune system and resist current cytotoxic therapies. Tumor recurrence then typically involves a rapid and deadly outcome. Understanding the mechanisms of glioma cell migration and designing novel targeting strategies are major challenges in devising more successful therapies against these tumors. Using a highly collaborative, multidisciplinary approach, we will investigate microenvironmental and topographic cues that direct glioma migration on biocompatible nanofibers designed to mimic the substrate topography within the brain.
Our specific aims are: 1) optimize a high-throughput in vitro migration assay using electrospun fiber mimicking nanoscale neural tissue topography to determine the potential of this model as a predictive bioassay of motility in ex vivo clinical glioma samples;2) utilize the high-throughput assay to explore mechanisms that direct migration of clinical glioma cells and molecular factors regulating motility;and 3) assay anti-migratory strategies against cell dispersion to determine the potential of this model as a predictive bioassay of motility in clinical glioma samples. To pursue these aims we will 1) produce high-throughput multiwell cell culture plates with aligned, electrospun nanofiber on the bottom to mimic the aligned structure of white matter, 2) analyze glioma cell migration and characterize the cellular/molecular changes that occur on nanofibers presenting different topographies, 3) investigate potential molecular targets and anti-migratory chemotherapeutics against glioma migration on these devices, and 4) analyze the migration of ex vivo tumor cells and test anti-migratory strategies on those samples to determine the potential of the nanofiber model as a predictive bioassay with immediate clinical relevance.
These aims address the goals and scope of the Small Business Catalyst Awards for Accelerating Innovative Research (R43) and are directly relevant to the health mission of the NIH while showing a large commercial potential. We expect that these studies will provide improved, more accurate models of glioma migration, having better predictive power and higher translational potential to improve public health. At the same time, we believe that our research may identify key factors that regulate glioma cell migration, potentially helping to devise a broad range of effective therapies against these devastating tumors. If this high-throughput motility assay is proven successful in this work, then it will provide an innovative tool to researchers from a large variety of backgrounds beyond gliomas.
Malignant brain tumors are highly invasive leading to infiltration of the surrounding normal brain tissue. This makes them extremely difficult or impossible to 'cure'even after surgical removal of the main tumor. Therapeutic targeting of this migrating cell population is thought to be essential if these diseases are to be managed effectively. In order to identify improved therapeutic approaches, we propose an innovative model using biocompatible nanofibers to mimic local aspects of brain structure that regulate glioma cell migration. We will use this novel model to assay clinical samples and predict strategies to prevent tumor recurrence. If proven successful, we propose that this innovative high-throughput device will have a large commercial value as it will help devise novel approaches that lead to improved patient outcomes.
|Agudelo-Garcia, Paula A; De Jesus, Jessica K; Williams, Shante P et al. (2011) Glioma cell migration on three-dimensional nanofiber scaffolds is regulated by substrate topography and abolished by inhibition of STAT3 signaling. Neoplasia 13:831-40|