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

这项NSF-NCI联合研究基金的目标是建立细胞外基质（ECM）刚度和微结构对肿瘤细胞侵袭的影响，并阐明这种调节背后的分子机制。虽然ECM刚度在控制肿瘤细胞迁移方面的强大影响已经在传统的二维培养范式中得到了很好的证实，但在更接近组织的三维（3D） ECM中理解这一现象已被证明更具挑战性。在某种程度上，这是因为改变3D ECM刚度的扰动通常同时改变微尺度基质参数，这些参数也对细胞迁移起到关键的调节作用，如孔径、纤维结构和局部材料的可变形性。通过将一种新的微尺度培养平台与基因靶向方法和计算建模相结合，该平台可以正交分离ECM刚度和孔几何形状，该项目将探索这两个参数对肿瘤细胞侵袭的贡献。这些研究最初将集中在多形性胶质母细胞瘤（GBM）上，这是一种高度恶性的脑肿瘤，通常在确诊后两年内导致患者死亡。这项工作的成功完成将为GBM的发展提供新的生物物理和机制见解，由此产生的实验和计算平台可能很容易应用于探索其他肿瘤类型的侵袭和转移。该项目还将以教育计划为特色，在该计划中，本科生将受到指导，并积极参与研究工作。最后，将为小学生创建一个关于细胞运动和ECM的学习模块，并通过一个地方项目进行教学，该项目将实践科学家和工程师安排在地区公立学校，以加强科学教育。

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.