Institute of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, 06108, Halle, Saale, Germany.
Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Straße 10, 13125, Berlin, Germany.
Cell Commun Signal. 2020 Jun 5;18(1):85. doi: 10.1186/s12964-020-00566-1.
Metastasis-associated in colon cancer 1 (MACC1) is an established marker for metastasis and tumor cell migration in a multitude of tumor entities, including glioblastoma (GBM). Nevertheless, the mechanism underlying the increased migratory capacity in GBM is not comprehensively explored.
We performed live cell and atomic force microscopy measurements to assess cell migration and mechanical properties of MACC1 overexpressing GBM cells. We quantified MACC1 dependent dynamics of 3D aggregate formation. For mechanistic studies we measured the expression of key adhesion molecules using qRT-PCR, and MACC1 dependent changes in short term adhesion to fibronectin and laminin. We then determined changes in sub-cellular distribution of integrins and actin in dependence of MACC1, but also in microtubule and intermediate filament organization.
MACC1 increased the migratory speed and elastic modulus of GBM cells, but decreased cell-cell adhesion and inhibited the formation of 3D aggregates. These effects were not associated with altered mRNA expression of several key adhesion molecules or altered short-term affinity to laminin and fibronectin. MACC1 did neither change the organization of the microtubule nor intermediate filament cytoskeleton, but resulted in increased amounts of protrusive actin on laminin.
MACC1 overexpression increases elastic modulus and migration and reduces adhesion of GBM cells thereby impeding 3D aggregate formation. The underlying molecular mechanism is independent on the organization of microtubules, intermediate filaments and several key adhesion molecules, but depends on adhesion to laminin. Thus, targeting re-organization of the cytoskeleton and cell motility via MACC1 may offer a treatment option to impede GBM spreading. Video Abstract.
结肠癌转移相关基因 1（MACC1）是多种肿瘤实体（包括胶质母细胞瘤（GBM））转移和肿瘤细胞迁移的公认标志物。然而，GBM 中迁移能力增加的机制尚未得到全面探讨。
我们进行了活细胞和原子力显微镜测量，以评估过表达 MACC1 的 GBM 细胞的迁移和机械特性。我们量化了 MACC1 依赖性 3D 聚集形成的动力学。为了进行机制研究，我们使用 qRT-PCR 测量了关键粘附分子的表达，并测量了 MACC1 依赖性对纤连蛋白和层粘连蛋白的短期粘附的变化。然后，我们确定了依赖于 MACC1 的整合素和肌动蛋白亚细胞分布的变化，以及微管和中间丝组织的变化。
MACC1 增加了 GBM 细胞的迁移速度和弹性模量，但降低了细胞-细胞粘附并抑制了 3D 聚集的形成。这些影响与几种关键粘附分子的 mRNA 表达改变或对层粘连蛋白和纤连蛋白的短期亲和力改变无关。MACC1 既没有改变微管的组织，也没有改变中间丝细胞骨架的组织，但导致在层粘连蛋白上有更多的突起肌动蛋白。
MACC1 的过表达增加了 GBM 细胞的弹性模量和迁移，并降低了细胞的粘附，从而阻碍了 3D 聚集的形成。潜在的分子机制独立于微管、中间丝和几种关键粘附分子的组织，而是依赖于对层粘连蛋白的粘附。因此，通过 MACC1 靶向细胞骨架和细胞运动的重新组织可能提供一种治疗选择，以阻止 GBM 的扩散。视频摘要。
