Nuclear export inhibition jumbles epithelial-mesenchymal states and gives rise to migratory disorder in healthy epithelia.
Nuclear export inhibition jumbles epithelial-mesenchymal states and gives rise to migratory disorder in healthy epithelia.
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DOI：
10.7554/elife.81048
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发表时间：
2023-02-21
期刊：
影响因子：
7.7
通讯作者：
Pathak A
中科院分区：
文献类型：
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作者：
Krull CM;Li H;Pathak A
E-M 因子的动态核质转运调节细胞 E-M 状态；然而，目前尚不清楚同时捕获这些因子如何在宏观尺度上影响上皮细胞。为了探索这个问题，我们通过瘦霉素 B 和 Selinexor 处理进行核输出抑制 (NEI)，这会偏向 CRM1 相关 E-M 因子的核定位。我们检查了一系列基质硬度下集体细胞表型的变化。 NEI 之后，软基质可提高 MCF10A 细胞的集体迁移长达 24 小时，而较硬的基质会在所有时间点减少迁移。我们的结果表明，NEI 通过细胞间粘附和机械激活之间的竞争来破坏迁移，通常会导致细胞间协调的丧失。具体来说，在不同的基底硬度上，NEI 促进非典型的 E-M 状态，其中 MCF10A 细胞变得更加上皮化和更加间质化。我们观察到 NEI 培养了一系列这些并发表型，从更多的上皮 shYAP MCF10A 细胞到更多的间充质 MDCK II 细胞。 α-连环蛋白作为 E-M 状态之间的潜在联系而出现，它维持细胞间粘附的正常水平并将机械活性特征传递给集体行为。最终，为了适应这里观察到的并发状态，我们提出了一个扩展的 E-M 模型，这可能有助于进一步理解基本的生物现象并为病理治疗提供信息。
Dynamic nucleocytoplasmic transport of E-M factors regulates cellular E-M states; yet, it remains unknown how simultaneously trapping these factors affects epithelia at the macroscale. To explore this question, we performed nuclear export inhibition (NEI) via leptomycin B and Selinexor treatment, which biases nuclear localization of CRM1-associated E-M factors. We examined changes in collective cellular phenotypes across a range of substrate stiffnesses. Following NEI, soft substrates elevate collective migration of MCF10A cells for up to 24 hr, while stiffer substrates reduce migration at all time points. Our results suggest that NEI disrupts migration through competition between intercellular adhesions and mechanoactivation, generally causing loss of cell–cell coordination. Specifically, across substrate stiffnesses, NEI fosters an atypical E-M state wherein MCF10A cells become both more epithelial and more mesenchymal. We observe that NEI fosters a range of these concurrent phenotypes, from more epithelial shYAP MCF10A cells to more mesenchymal MDCK II cells. α-Catenin emerges as a potential link between E-M states, where it maintains normal levels of intercellular adhesion and transmits mechanoactive characteristics to collective behavior. Ultimately, to accommodate the concurrent states observed here, we propose an expanded E-M model, which may help further understand fundamental biological phenomena and inform pathological treatments.