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

这项NSF-NCI联合研究资助的目标是建立细胞外基质（ECM）硬度和微结构对肿瘤细胞侵袭的影响，并阐明这种调节的分子机制。 虽然ECM刚度在控制肿瘤细胞迁移中的强烈影响已经在传统的二维培养范例中得到了很好的建立，但在更接近模拟组织的三维（3D）ECM中理解这种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也严格调节细胞迁移的微尺度基质参数，例如孔径、纤维结构和局部材料变形性。 通过结合一种新的微尺度培养平台，使ECM刚度和孔几何形状的正交分离与基因靶向方法和计算建模，该项目将探索这两个参数对肿瘤细胞侵袭的贡献。研究将首先集中在多形性胶质母细胞瘤（GBM），一种高度恶性的脑肿瘤，通常在诊断后两年内杀死患者。 这项工作的成功完成将为GBM的进展提供新的生物物理学和机制见解，并且由此产生的实验和计算平台可以很容易地应用于探测其他肿瘤类型的侵袭和转移。 该项目还将包括一个教育计划，其中本科生将得到指导，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，并通过一个当地项目进行教学，该项目将在地区公立学校中实习的科学家和工程师安置在一起，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.