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Tissue-Engineered Tumor Models for Drug Discovery and Development
Thu, May 25, 2017, 6:00 PM – 7:30 PM EDT
Biology is dynamic and three-dimensional; therefore, why are we still using static, two-dimensional models? Moving away from 2D tissue culture toward more physiologically relevant 3D tumor models is required to bridge the gap between in-vitro and in-vivo studies. Such models should provide physiologically predictive results; direct, more efficient and effective in-vivo studies, and improve translation for clinical trial safety and effectiveness. Significant efforts have focused on a cell-centric understanding of cancer, yet much less effort has been placed on fully characterizing the relationships and interdependence among invasive metastatic behavior and the physicochemical properties of the extracellular matrix (ECM).
An unmet need exist for tunable in-vitro and in-vivo models of metastatic melanoma that allow for high-resolution investigation of cell-ECM interactions and prediction of metastatic invasion with high reproducibility and control. Utilizing tissue engineering fabrication strategies, we are creating well-defined melanoma cell-laden ECM constructs to study tumor progression phenomena at cellular-level scales under a multitude of conditions. Constructs composed of collagen, fibronectin, laminin, elastin and other ECM constituent materials have been fabricated with controlled physical and structural properties to recapitulate that observed in native tumor microenvironments.
Advanced biomaterials characterization strategies including Raman spectroscopy and atomic force microscopy have been applied to assess the effect of physicochemical properties on tumor progression, as well as how these properties change over time. Conventional biological and cell-based assays, such as PCR and immunocytochemistry, have also been performed to assess the cell phenotype and demonstrate reproducibility and physiological fidelity of the tissue-engineered tumor models. The models have been utilized to demonstrate proof-of-concept application as robust platforms for studying the effects of a novel nanomaterial therapeutic known to effect prometastatic ECM-related pathways and inhibit tumor progression.
Future work will use this model platform for predicting the physicochemical factors influencing invasion and metastasis in vivo via implantation in animal models. Additionally, more complex ECM constructs will also be developed, including the introduction of vascular components via microfabrication, as well as the study of a variety of other tumor types to demonstrate the platform’s flexibility. This work will yield a reproducible model system that enables in-vitro-to-in-vivo translational validation and yield a discovery platform for innovative ECM therapeutic targets.