Biomechanics of the Nucleus in Confined Migration

细胞核受限迁移的生物力学

• 批准号: 1929412
• 负责人: giuliano scarcelli
• 金额: $ 32.2万
• 依托单位: University of Maryland, College Park
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-11-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1929412&HistoricalAwards=false
• 关键词: Biomechanics; Nucleus; Confined; Migration

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.

当细胞需要穿过狭小的空间时，它需要改变其形状以适应开口。 在此过程中，细胞核的变形是一个严峻的挑战，因为细胞核是细胞最大、最坚硬的部分。较软的细胞核有望使这种穿过小空间的运动变得更容易，因为它允许细胞更大程度地变形。 然而，调节细胞核硬度变化的已知因素的行为与这种简单的情况不一致，并且表明了一种尚未理解的更复杂的情况。 该项目旨在通过使用新颖的机械测试技术探测细胞迁移过程中的核力学（包括穿过小空间）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记。 因此，它可用于探测物理上无法接近的迁移细胞的细胞核。从该项目中获得的知识将支持进一步了解癌细胞如何侵入健康组织和转移。 这个跨学科项目还将为工程本科生提供实践教育课程的机会，以设计和构建用于生物医学应用的先进光子仪器。有限微环境中的细胞迁移对于许多过程至关重要，例如组织发育和免疫细胞运输，并且，代表了转移扩散的严峻挑战。该项目将能够使用布里渊显微镜直接测量受限细胞迁移过程中核机械特性的动态变化。 经过验证的技术将用于测量核模量调节及其细胞内调节剂，首先响应微环境的物理信号，然后在通过受限微环境的迁移过程中。 因此，这项研究将揭示核的机械特性，有利于通过小收缩的迁移；具体来说，它将识别转移级联中至关重要的核特性，并描述它们在转移进展过程中如何演变。通过该项目获得的基础知识的改进可能最终会导致基于核力学表型的转移的新诊断和治疗目标。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查进行评估，被认为值得支持标准。

项目成果

Water transport regulates nucleus volume, cell density, Young’s modulus, and E-cadherin expression in tumor spheroids

水运输调节肿瘤球体中的细胞核体积、细胞密度、杨氏模量和 E-钙粘蛋白表达

• DOI: 10.1016/j.ejcb.2022.151278
• 发表时间: 2022-09
• 期刊: European Journal of Cell Biology
• 影响因子: 6.6
• 作者: Conrad, Christina;Conway, Jessica;Polacheck, William J.;Rizvi, Imran;Scarcelli, Giuliano
• 通讯作者: Scarcelli, Giuliano

Optical Focusing beyond the Diffraction Limit via Vortex-Assisted Transient Microlenses

通过涡旋辅助瞬态微透镜实现超越衍射极限的光学聚焦

• DOI: 10.1021/acsphotonics.0c00109
• 发表时间: 2020-03-19
• 期刊: ACS Photonics
• 影响因子: 7
• 作者: Eitan Edrei;G. Scarcelli
• 通讯作者: G. Scarcelli

Tumor cell nuclei soften during transendothelial migration

肿瘤细胞核在跨内皮迁移过程中软化

• DOI: 10.1016/j.jbiomech.2021.110400
• 发表时间: 2021-05-24
• 期刊: Journal of Biomechanics
• 影响因子: 2.4
• 作者: Roberts AB;Zhang J;Raj Singh V;Nikolić M;Moeendarbary E;Kamm RD;So PTC;Scarcelli G
• 通讯作者: Scarcelli G

Dorsoventral polarity directs cell responses to migration track geometries

背腹极性指导细胞对迁移轨迹几何形状的反应

• DOI: 10.1126/sciadv.aba6505
• 发表时间: 2020-07-01
• 期刊: Science Advances
• 影响因子: 13.6
• 作者: Emily O. Wisniewski;P. Mistriotis;K. Bera;Robert A Law;Jitao Zhang;Miloš Nikolić;Michael Weiger;Maria Parlani;Soontorn Tuntithavornwat;A. Afthinos;Runchen Zhao;D. Wirtz;P. Kalab;G. Scarcelli;P. Friedl;K. Konstantopoulos
• 通讯作者: K. Konstantopoulos

Nuclear Mechanics within Intact Cells Is Regulated by Cytoskeletal Network and Internal Nanostructures

完整细胞内的核力学受细胞骨架网络和内部纳米结构的调节

• DOI: 10.1002/smll.201907688
• 发表时间: 2020-05
• 期刊: Small
• 影响因子: 13.3
• 作者: Zhang J;Alisafaei F;Nikolić M;Nou XA;Kim H;Shenoy VB;Scarcelli G
• 通讯作者: Scarcelli G