Increased Stiffness Inhibits Invadopodia Formation and Cell Migration in 3D
Increased Stiffness Inhibits Invadopodia Formation and Cell Migration in 3D
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DOI：
10.1016/j.bpj.2020.07.003
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发表时间：
2020-08-18
影响因子：
3.4
通讯作者：
Chaudhuri, Ovijit
中科院分区：
文献类型：
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作者：
Chang, Julie;Pang, Emily M.;Chaudhuri, Ovijit
癌细胞通常在转移期间的关键点通过基底膜（BM）侵入，包括原发性肿瘤侵入、内渗和外渗。细胞延伸侵入伪足突起以在纳米多孔BM中产生通道，通过该通道它们可以经由蛋白水解降解或机械力侵入。增加的基质硬度可以促进癌症进展，并且二维（2D）培养研究表明增加的硬度促进侵袭伪足降解活性。然而，侵袭伪足可以机械地起作用，独立于它们的降解活性，并且细胞不会形成完全成熟的侵袭伪足或在2D环境中沿着侵袭伪足的方向迁移。在这里，我们阐明了矩阵刚度的机械模式的侵袭伪足活动的三维BM样矩阵中培养的癌细胞的影响。侵袭伪足的形成和细胞迁移测定进行的侵袭性乳腺癌细胞培养在机械塑料，纳米多孔，和最低限度的可降解的互穿网络的重建BM基质和藻酸盐，这提出了一系列的弹性模量从0.4到9.3千帕。在整个硬度范围内，我们发现细胞形成成熟的侵入伪足，通常先于突起方向的迁移。然而，在更高的刚度，细胞形成更短和更短暂的侵入伪足，不太可能扩大侵入伪足整体，从2D研究的结果相比。随后，细胞迁移在僵硬的环境中减少。因此，虽然以前的研究表明，增加刚度可能会促进恶性表型和invadopodia的降解活性，我们的研究结果表明，增加刚度物理限制invadopodia的扩展和细胞迁移在三维，BM样环境。
Cancer cells typically invade through basement membranes (BMs) at key points during metastasis, including primary tumor invasion, intravasation, and extravasation. Cells extend invadopodia protrusions to create channels in the nanoporous BM through which they can invade, either via proteolytic degradation or mechanical force. Increased matrix stiffness can promote cancer progression, and two-dimensional (2D) culture studies indicate that increased stiffness promotes invadopodia degradation activity. However, invadopodia can function mechanically, independent of their degradative activity, and cells do not form fully matured invadopodia or migrate in the direction of the invadopodia in 2D environments. Here, we elucidated the impact of matrix stiffness on the mechanical mode of invadopodia activity of cancer cells cultured in three-dimensional BM-like matrices. Invadopodia formation and cell migration assays were performed for invasive breast cancer cells cultured in mechanically plastic, nanoporous, and minimally degradable interpenetrating networks of reconstituted BM matrix and alginate, which presented a range of elastic moduli from 0.4 to 9.3 kPa. Across this entire range of stiffness, we find that cells form mature invadopodia that often precede migration in the direction of the protrusion. However, at higher stiffness, cells form shorter and more transient invadopodia and are less likely to extend invadopodia overall, contrasting with results from 2D studies. Subsequently, cell migration is diminished in stiff environments. Thus, although previous studies indicate that increased stiffness may promote malignant phenotypes and the degradative activity of invadopodia, our findings show that increased stiffness physically restricts invadopodia extension and cell migration in three-dimensional, BM-like environments.