Contractility, focal adhesion orientation, and stress fiber orientation drive cancer cell polarity and migration along wavy ECM substrates
Contractility, focal adhesion orientation, and stress fiber orientation drive cancer cell polarity and migration along wavy ECM substrates
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DOI：
10.1073/pnas.2021135118
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发表时间：
2021-06-01
影响因子：
11.1
通讯作者：
Waterman, Clare M.
中科院分区：
文献类型：
--
作者：
Fischer, Robert S.;Sun, Xiaoyu;Waterman, Clare M.
接触引导是一种强大的地形提示，可诱导持续的定向细胞迁移。健康组织基质的特征是波状细胞外基质（ECM）纤维束的网状结构，而易于转移的基质则表现出较少的波状、更多的线性纤维。后者的拓扑结构与不良预后相关，而更多的波状束与良性肿瘤相关。我们设计了纳米形貌 ECM 涂层基底，模拟肿瘤和健康组织中的胶原纤维波形，以确定这些纳米形貌如何调节癌细胞极化和迁移机制。细胞极化和定向迁移被高于阈值幅度的原纤维样波基质抑制。尽管低振幅波基底上的极化和迁移需要极性信号和肌动蛋白成核因子，但它们并不定位于细胞前缘。相反，这些因素局限于波峰，在细胞内产生多个“神秘的前缘”。在高振幅波基底上，来自大隐秘前缘的逆行流使应力纤维和粘着斑去极化并抑制细胞迁移。在低振幅波基底上，肌动球蛋白的收缩性超越了小的隐秘前缘，并沿着波轴驱动应力纤维和粘着斑方向以介导定向迁移。具有不同内在收缩性的癌细胞在不同的波幅下去极化，并且可以通过操纵收缩性来调节细胞对波状基质的极化响应。我们提出，肿瘤周围具有足够高振幅的 ECM 原纤维波形可以充当“细胞极化屏障”，减少肿瘤细胞的定向迁移，这可以通过上调肿瘤细胞收缩性来克服。
Contact guidance is a powerful topographical cue that induces persistent directional cell migration. Healthy tissue stroma is characterized by a meshwork of wavy extracellular matrix (ECM) fiber bundles, whereas metastasis-prone stroma exhibit less wavy, more linear fibers. The latter topography correlates with poor prognosis, whereas more wavy bundles correlate with benign tumors. We designed nanotopographic ECM-coated substrates that mimic collagen fibril waveforms seen in tumors and healthy tissues to determine how these nanotopographies may regulate cancer cell polarization and migration machineries. Cell polarization and directional migration were inhibited by fibril-like wave substrates above a threshold amplitude. Although polarity signals and actin nucleation factors were required for polarization and migration on low-amplitude wave substrates, they did not localize to cell leading edges. Instead, these factors localized to wave peaks, creating multiple "cryptic leading edges" within cells. On high amplitude wave substrates, retrograde flow from large cryptic leading edges depolarized stress fibers and focal adhesions and inhibited cell migration. On low-amplitude wave substrates, actomyosin contractility overrode the small cryptic leading edges and drove stress fiber and focal adhesion orientation along the wave axis to mediate directional migration. Cancer cells of different intrinsic contractility depolarized at different wave amplitudes, and cell polarization response to wavy substrates could be tuned by manipulating contractility. We propose that ECM fibril waveforms with sufficiently high amplitude around tumors may serve as "cell polarization barriers," decreasing directional migration of tumor cells, which could be overcome by up-regulation of tumor cell contractility.