Introduction

The extracellular matrix (ECM) in the tumor microenvironment contains high densities of collagen that are highly aligned, resulting in directional migration called contact guidance that facilitates efficient migration out of the tumor. Cancer cells can remodel the ECM through traction force controlled by myosin contractility or proteolytic activity controlled by matrix metalloproteinase (MMP) activity, leading to either enhanced or diminished contact guidance.

Methods

Recently, we have leveraged the ability of mica to epitaxially grow aligned collagen fibrils in order to assess contact guidance. In this article, we probe the mechanisms of remodeling of aligned collagen fibrils on mica by breast cancer cells.

Results

We show that cells that contact guide with high fidelity (MDA-MB-231 cells) exert more force on the underlying collagen fibrils than do cells that contact guide with low fidelity (MTLn3 cells). These high traction cells (MDA-MB-231 cells) remodel collagen fibrils over hours, pulling so hard that the collagen fibrils detach from the surface, effectively delaminating the entire contact guidance cue. Myosin or MMP inhibition decreases this effect. Interestingly, blocking MMP appears to increase the alignment of cells on these substrates, potentially allowing the alignment through myosin contractility to be uninhibited. Finally, amplification or dampening of contact guidance with respect to a particular collagen fibril organization is seen under different conditions.

Conclusions

Both myosin II contractility and MMP activity allow MDA-MB-231 cells to remodel and eventually destroy epitaxially grown aligned collagen fibrils.

中文翻译：

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外延生长的胶原原纤维的降解和重塑。

介绍

肿瘤微环境中的细胞外基质 (ECM) 含有高度排列的高密度胶原蛋白，导致称为接触引导的定向迁移，有助于有效迁移出肿瘤。癌细胞可以通过肌球蛋白收缩力控制的牵引力或基质金属蛋白酶 (MMP) 活性控制的蛋白水解活性来重塑 ECM，从而增强或减弱接触引导。

方法

最近，我们利用云母外延生长对齐胶原纤维的能力来评估接触引导。在本文中，我们探讨了乳腺癌细胞重塑云母上排列的胶原纤维的机制。

结果

我们发现，与低保真度接触导板的细胞（MTLn3 细胞）相比，高保真度接触导板的细胞（MDA-MB-231 细胞）对底层胶原纤维施加更大的力。这些高牵引力细胞（MDA-MB-231 细胞）会在数小时内重塑胶原纤维，拉力如此之大，以至于胶原纤维从表面分离，从而有效地使整个接触引导提示分层。抑制肌球蛋白或 MMP 会减弱这种作用。有趣的是，阻断 MMP 似乎会增加细胞在这些基质上的排列，从而可能使通过肌球蛋白收缩性的排列不受抑制。最后，在不同条件下观察到针对特定胶原原纤维组织的接触引导的放大或减弱。

结论

肌球蛋白 II 收缩性和 MMP 活性使 MDA-MB-231 细胞能够重塑并最终破坏外延生长的对齐胶原纤维。