CD44-mediated adhesion to hyaluronic acid contributes to mechanosensing and invasive motility.
CD44-mediated adhesion to hyaluronic acid contributes to mechanosensing and invasive motility.
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DOI：
10.1158/1541-7786.mcr-13-0629
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发表时间：
2014-10
期刊：
影响因子：
--
通讯作者：
Kumar S
中科院分区：
文献类型：
--
作者：
Kim Y;Kumar S
高分子量的糖胺聚糖，透明质酸（HA），构成脑细胞外基质（ECM）的重要部分。多形性胶质母细胞瘤（GBM）是一种高度侵袭性的脑肿瘤，与HA分泌异常、组织硬化和HA受体CD 44过表达相关。在这里，转录组学分析，工程材料，粘附，迁移和侵袭的测量被用来研究HA/CD 44连接如何有助于GBM肿瘤细胞的机械感应和侵入性运动，无论是内在的还是在RGD/整联蛋白粘附的背景下。来自癌症基因组图谱（TCGA）的转录组数据的分析揭示了与HA/CD 44粘附相关的转录物的上调。即使存在RGD，培养物中的CD 44抑制也会在短时间尺度上（孵育后0.5小时）降低细胞与HA的粘附，而在较长时间尺度上（3小时）的最大粘附需要CD 44和整联蛋白两者。此外，延时成像表明，在裸HA基质上迁移期间形成的细胞粘附结构比在含有RGD的表面上形成的细胞突起更短命。有趣的是，粘附和迁移速度依赖于HA水凝胶刚度，这意味着基于CD 44的信号传导本质上是机械敏感的。最后，CD 44的表达配对HA丰富的微环境最大化的三维invasion，而CD 44的抑制或丰富的整合素为基础的粘附限制it. These研究结果表明，CD 44转导HA为基础的刚度线索，暂时领先于整合素为基础的粘附成熟，并促进入侵。
The high molecular weight glycosaminoglycan, hyaluronic acid (HA), makes up a significant portion of the brain extracellular matrix (ECM). Glioblastoma multiforme (GBM), a highly invasive brain tumor, is associated with aberrant HA secretion, tissue stiffening, and overexpression of the HA receptor CD44. Here, transcriptomic analysis, engineered materials, and measurements of adhesion, migration, and invasion were used to investigate how HA/CD44 ligation contributes to the mechanosensing and invasive motility of GBM tumor cells, both intrinsically and in the context of RGD/integrin adhesion. Analysis of transcriptomic data from The Cancer Genome Atlas (TCGA) reveals up-regulation of transcripts associated with HA/CD44 adhesion. CD44 suppression in culture reduces cell adhesion to HA on short time scales (0.5h post-incubation) even if RGD is present, whereas maximal adhesion on longer time scales (3h) requires both CD44 and integrins. Moreover, time-lapse imaging demonstrates that cell adhesive structures formed during migration on bare HA matrices are more short-lived than cellular protrusions formed on surfaces containing RGD. Interestingly, adhesion and migration speed were dependent on HA hydrogel stiffness, implying that CD44-based signaling is intrinsically mechanosensitive. Finally, CD44 expression paired with an HA-rich microenvironment maximized three-dimensional invasion, whereas CD44 suppression or abundant integrin-based adhesion limited it. These findings demonstrate that CD44 transduces HA-based stiffness cues, temporally precedes integrin-based adhesion maturation, and facilitates invasion.