A broad challenge in cancer biology is the development of cell culture models that are physiologically relevant in that the resident cells display the complex behaviors that underiie disease. Further, cell culture models that provide a uniform and consistent microenvironment to the cells will decrease the distribution of cellular behaviors that are typically observed and therefore will lead to robust assays that can be used to quantitatively compare the behaviors of different cell populations. The proposed work is intended to improve on the use of planar cultures performed on plastic dishes that are often insufficient to capture relevant cell behaviors, and the common Matrigel three-dimensional matrix that has been important to cancer biology, notwithstanding the variable properties of and incompletely defined composition of this natural matrix. The proposed project will pursue molecular approaches to developing two classes of defined matrices. One is based on nanopatterned substrates and is significant because the patterns can be used to constrain the sizes of focal adhesionsmaking them more relevant to what is observed in cells within tissueand when arranged into track patterns provides a reproducible path for cells to migrate along, removing a large source of heterogeneous behavior. The second approach is based on three-dimensional matrices that are selfassembled from peptides and peptide amphiphiles and is significant for the use of a completely defined composition that also permits wide flexibility in incorporating peptide and protein motifs. Both designs emphasize the control of material properties at the nanoscaleeither in the dimensions of patterned extracellular matrix or the sizes of the fibrils in the three dimensional matricesand therefore mimic the physical features of protein matrix. The project emphasizes the development and characterization of the matrices, but also includes investigators with expertise in the biology and medicine of brain and pancreafic cancer, providing a real test-bed for evaluating the matrices. The broad goal of the project is to develop culture systems that are unmatched for providing cells with a microenvironment that supports complex biological functions and that enable robust, quantitative assays of cell function. This work, if successful, will therefore be important in basic research laboratories but also in programs to use cell-based assays in high throughput screens and possibly as materials that provide for regeneration of tissue in the treatment of cancer.
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