Glioblastoma Cells Use an Integrin- and CD44-Mediated Motor-Clutch Mode of Migration in Brain Tissue

IF 2.3 4区医学 Q3 BIOPHYSICS

Cellular and molecular bioengineering Pub Date : 2024-03-04 DOI:10.1007/s12195-024-00799-x

Sarah M. Anderson, Marcus Kelly, David J. Odde

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引用次数: 0

Abstract

Purpose

Glioblastoma (GBM) is an aggressive malignant brain tumor with 2 year survival rates of 6.7% (Stupp et al. in J Clin Oncol Off J Am Soc Clin Oncol 25:4127–4136, 2007; Mohammed et al. in Rep Pract Oncol Radiother 27:1026–1036, 2002). One key characteristic of the disease is the ability of glioblastoma cells to migrate rapidly and spread throughout healthy brain tissue (Lefranc et al. in J Clin Oncol Off J Am Soc Clin Oncol 23:2411–2422, 2005; Hoelzinger et al. in J Natl Cancer Inst 21:1583–1593, 2007). To develop treatments that effectively target cell migration, it is important to understand the fundamental mechanism driving cell migration in brain tissue. Several models of cell migration have been proposed, including the motor-clutch, bleb-based motility, and osmotic engine models.

Methods

Here we utilized confocal imaging to measure traction dynamics and migration speeds of glioblastoma cells in mouse organotypic brain slices to identify the mode of cell migration.

Results

We found that nearly all cell-vasculature interactions reflected pulling, rather than pushing, on vasculature at the cell leading edge, a finding consistent with a motor-clutch mode of migration, and inconsistent with an osmotic engine model or confined bleb-based migration. Reducing myosin motor activity, a key component in the motor-clutch model, was found to decrease migration speed at high doses for all cell types including U251 and 6 low-passage patient-derived xenograft lines (3 proneural and 3 mesenchymal subtypes). Variable responses were found at low doses, consistent with a motor-clutch mode of migration which predicts a biphasic relationship between migration speed and motor-to-clutch ratio. Targeting of molecular clutches including integrins and CD44 slowed migration of U251 cells.

Conclusions

Overall we find that glioblastoma cell migration is most consistent with a motor-clutch mechanism to migrate through brain tissue ex vivo, and that both integrins and CD44, as well as myosin motors, play an important role in constituting the adhesive clutch.

Abstract Image

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胶质母细胞瘤细胞利用整合素和 CD44 介导的马达离合器模式在脑组织中迁移

目的胶质母细胞瘤（GBM）是一种侵袭性恶性脑肿瘤，2 年生存率仅为 6.7%（Stupp 等人，发表于 J Clin Oncol Off J Am Soc Clin Oncol 25:4127-4136, 2007；Mohammed 等人，发表于 Rep Pract Oncol Radiother 27:1026-1036, 2002）。这种疾病的一个主要特征是胶质母细胞瘤细胞能够快速迁移并扩散到整个健康的脑组织（Lefranc 等，发表于 J Clin Oncol Off J Am Soc Clin Oncol 23:2411-2422, 2005；Hoelzinger 等，发表于 J Natl Cancer Inst 21:1583-1593, 2007）。要开发出有效针对细胞迁移的治疗方法，就必须了解驱动脑组织细胞迁移的基本机制。方法我们利用共聚焦成像技术测量了胶质母细胞瘤细胞在小鼠有机脑切片中的牵引动态和迁移速度，以确定细胞迁移的模式。结果我们发现，几乎所有细胞与血管的相互作用都反映了细胞前缘对血管的牵引而非推动，这一发现与马达离合器迁移模式一致，而与渗透引擎模式或封闭的蚕泡迁移模式不一致。降低肌球蛋白马达活性是马达离合器模式的关键组成部分，研究发现，高剂量可降低所有细胞类型的迁移速度，包括 U251 和 6 个低通过率患者衍生异种移植系（3 个软骨亚型和 3 个间充质亚型）。在低剂量时发现了不同的反应，这与马达-离合器迁移模式一致，该模式预测了迁移速度与马达-离合器比率之间的双相关系。结论总之，我们发现胶质母细胞瘤细胞的迁移最符合体内通过脑组织迁移的马达-离合器机制，而整合素和 CD44 以及肌球蛋白马达在构成粘附离合器方面发挥着重要作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cellular and molecular bioengineering 生物-生物物理

CiteScore

5.60

自引率

3.60%

发文量

审稿时长

>12 weeks

期刊介绍： The field of cellular and molecular bioengineering seeks to understand, so that we may ultimately control, the mechanical, chemical, and electrical processes of the cell. A key challenge in improving human health is to understand how cellular behavior arises from molecular-level interactions. CMBE, an official journal of the Biomedical Engineering Society, publishes original research and review papers in the following seven general areas: Molecular: DNA-protein/RNA-protein interactions, protein folding and function, protein-protein and receptor-ligand interactions, lipids, polysaccharides, molecular motors, and the biophysics of macromolecules that function as therapeutics or engineered matrices, for example. Cellular: Studies of how cells sense physicochemical events surrounding and within cells, and how cells transduce these events into biological responses. Specific cell processes of interest include cell growth, differentiation, migration, signal transduction, protein secretion and transport, gene expression and regulation, and cell-matrix interactions. Mechanobiology: The mechanical properties of cells and biomolecules, cellular/molecular force generation and adhesion, the response of cells to their mechanical microenvironment, and mechanotransduction in response to various physical forces such as fluid shear stress. Nanomedicine: The engineering of nanoparticles for advanced drug delivery and molecular imaging applications, with particular focus on the interaction of such particles with living cells. Also, the application of nanostructured materials to control the behavior of cells and biomolecules.