Mechanosensitive Tumor Cell Migration: Deconstructing the Roles of Matrix Stiffness and Confinement

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The goals of this NSF-NCI joint research grant are to establish the influence of extracellular matrix (ECM) stiffness and microarchitecture on tumor cell invasion and to elucidate the molecular mechanisms that underlie this regulation. While the strong influence of ECM stiffness in governing tumor cell migration has been well established in traditional two-dimensional culture paradigms, understanding this phenomenon in three-dimensional (3D) ECMs that more closely mimic tissue has proven considerably more challenging. In part, this is because perturbations that change 3D ECM stiffness often concurrently change microscale matrix parameters that also critically regulate cell migration, such as pore size, fiber architecture, and local material deformability. By combining a new microscale culture platform that enables orthogonal separation of ECM stiffness and pore geometry with gene targeting approaches and computational modeling, this project will explore the contributions of these two parameters to the invasion of tumor cells.The studies will initially focus on glioblastoma multiforme (GBM), a highly malignant brain tumor that routinely kills patients within two years of diagnosis. Successful completion of the work will provide new biophysical, mechanistic insight into the progression of GBM, and the resulting experimental and computational platforms may be readily applied to probe the invasion and metastasis of other tumor types. The project will also feature an educational plan in which undergraduates will be mentored and actively included in research efforts. Finally, a learning module for elementary school students on cell motility and the ECM will be created and taught through a local program that places practicing scientists and engineers in area public schools to enhance science education.