Biomechanics of the Nucleus in Confined Migration

当细胞需要在小空间中移动时，它需要改变形状以适应开口。在这个过程中，细胞核的变形是一个关键的挑战，因为细胞核是细胞中最大和最坚硬的部分。更柔软的细胞核有望使这种通过小空间的运动更容易，因为它将允许细胞在更大程度上变形。然而，调节细胞核刚度变化的已知因素的行为与这种简单的情况不一致，并表明一个尚未理解的更复杂的情况。该项目旨在通过使用一种新颖的机械测试技术，在细胞迁移过程中探测核力学，包括通过小空间，来填补这一知识空白。该技术不需要与细胞接触，也不需要使用外部标签。因此，它可以用来探测迁移细胞的细胞核，这是物理上无法接近的。从该项目中获得的知识将有助于进一步了解癌细胞如何侵入健康组织并转移。这个跨学科的项目也将提供一个机会，为工程本科学生设计和建造用于生物医学应用的先进光子仪器提供实践教育课程。细胞在受限微环境中的迁移是许多过程的核心，如组织发育和免疫细胞运输，并且是转移性扩散的关键挑战。该项目将能够使用布里渊显微镜直接测量在受限细胞迁移过程中核力学性能的动态变化。经过验证的技术将用于测量核模量调制及其细胞内调节因子，首先响应微环境的物理线索，然后在通过受限微环境的迁移过程中。因此，这项研究将揭示有利于通过小收缩迁移的核的机械特性；具体来说，它将确定在转移级联中至关重要的核性质，并描述它们在转移过程中如何演变。通过本项目获得的基础知识的改进可能最终导致基于核力学表型的新的转移诊断和治疗靶点。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

When a cell needs to migrate through small spaces, it needs to change its shape to fit through the opening. During this process, deformation of the nucleus represents a critical challenge, since the nucleus is the largest and stiffest part of a cell. A softer nucleus is expected to make this movement through small spaces easier, because it would allow the cell to deform to a greater extent. However, the behavior of known factors that regulate changes in the stiffness of the nucleus is inconsistent with this simple scenario and suggests a more complex situation that is not yet understood. This project aims to fill this knowledge gap by probing nuclear mechanics during cellular migration, including through small spaces, using a novel mechanical testing technique. This technique does not require contact with the cell nor the use of external labels. Thus, it can be used to probe the nucleus of migrating cells, which are not physically accessible. The knowledge gained from this project will support advancements in understanding of how cancer cells invade healthy tissue and metastasize. This interdisciplinary project will also provide an opportunity to implement hands-on educational courses for undergraduate engineering students to design and build advanced photonic instrumentation for biomedical applications.Cell migration in confined microenvironments is central to many processes, such as tissue development and immune cell trafficking, and, represents a critical challenge for metastatic spreading. This project will enable direct measurements of dynamic changes in nuclear mechanical properties during confined cell migration using Brillouin microscopy. The validated technique will be used measure nuclear modulus modulation and its intracellular regulators, first in response to physical cues of the microenvironment and then during migration through a confined microenvironment. Thus, this research will unveil the mechanical properties of the nucleus that are advantageous for migration through small constrictions; specifically, it will identify nuclear properties that are critical within the metastatic cascade and characterize how they evolve during metastatic progression. The improved fundamental knowledge gained with this project may ultimately lead to new diagnostic and therapeutic targets for metastasis based on phenotyping of nuclear mechanics.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.