Biomechanics of the Nucleus in Confined Migration

当细胞需要在狭小的空间中迁移时，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、最坚硬的部分。一个较软的细胞核有望使这种在狭小空间中的移动变得更容易，因为它将允许细胞在更大程度上变形。然而，调节原子核硬度变化的已知因素的行为与这个简单的情景不一致，并暗示了一个尚不清楚的更复杂的情况。该项目旨在通过使用一种新的机械测试技术，通过探测细胞迁移过程中的核力学，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，它可以用来探测物理上无法接触到的迁移细胞的核。从这个项目中获得的知识将支持对癌细胞如何侵入健康组织和转移的理解的进步。这一跨学科项目还将为工科本科生提供实施实践教育课程的机会，以设计和制造用于生物医学应用的先进光子仪器。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贩运，并且是转移扩散的关键挑战。该项目将使用布里渊显微镜直接测量受限细胞迁移过程中核力学性质的动态变化。这项经过验证的技术将用于测量核模数调制及其细胞内调节因子，首先响应微环境的物理线索，然后在有限的微环境中迁移。因此，这项研究将揭示有利于通过微小狭窄进行迁移的核的力学性质；具体地说，它将确定在转移级联中至关重要的核性质，并表征它们在转移过程中如何演变。从这个项目中获得的改进的基础知识最终可能导致基于核力学表型的新的转移诊断和治疗目标。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.