Rho activation drives luminal collapse and eversion in epithelial acini
Rho activation drives luminal collapse and eversion in epithelial acini
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Rho 激活驱动上皮腺泡管腔塌陷和外翻
DOI：
10.1016/j.bpj.2023.01.005
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发表时间：
2023
影响因子：
3.4
通讯作者：
Lele, Tanmay P.
中科院分区：
文献类型：
--
作者：
Narayanan, Vani;Purkayastha, Purboja;Yu, Bo;Pendyala, Kavya;Chukkapalli, Sasanka;Cabe, Jolene I.;Dickinson, Richard B.;Conway, Daniel E.;Lele, Tanmay P.
腺体内的上皮细胞和生长在柔软的细胞外基质中的细胞极化，顶端蛋白暴露在管腔内，而基础蛋白与细胞外基质接触。极性的改变，包括顶端向外的极性，发生在人类癌症中。尽管一些异常的极性状态可能是由于蛋白质运输的改变造成的，但最近对组织水平的异常内向外展开的观察表明，极性改变有另一种途径。由于机械改变在人类癌症中很常见，包括在腺泡上皮中rhoa介导的肌动球蛋白张力的上调，我们探讨了机械稳态的紊乱是否会导致根尖外翻。正常和肿瘤上皮腺泡中RhoA的直接激活，或通过阻断β1整合素、破坏LINC复合体、致癌Ras激活或Rac1抑制间接激活RhoA，都能强烈诱导腺泡外翻。此外，激光消融部分未经治疗的腺泡足以诱导外翻。对腺泡细胞的分析显示，相对于基底表面，顶端细胞表面有高曲率和低磷酸化的肌球蛋白。一个基于顶点的数学模型平衡了细胞-细胞界面的张力，结果显示基底细胞的表面张力比顶端细胞的表面张力大5倍。该模型表明，腺泡外翻的驱动力是腺泡顶面和基底面的表面能差。我们的研究结果提出了一种可能性，即机械稳态的丧失可能导致人类癌症的尖向外极性状态。
Epithelial cells lining a gland and cells grown in a soft extracellular matrix polarize with apical proteins exposed to the lumen and basal proteins in contact with the extracellular matrix. Alterations to polarity, including an apical-out polarity, occur in human cancers. Although some aberrant polarity states may result from altered protein trafficking, recent observations of an extraordinary tissue-level inside-out unfolding suggest an alternative pathway for altered polarity. Because mechanical alterations are common in human cancer, including an upregulation of RhoA-mediated actomyosin tension in acinar epithelia, we explored whether perturbing mechanical homeostasis could cause apical-out eversion. Acinar eversion was robustly induced by direct activation of RhoA in normal and tumor epithelial acini, or indirect activation of RhoA through blockage of β1-integrins, disruption of the LINC complex, oncogenic Ras activation, or Rac1 inhibition. Furthermore, laser ablation of a portion of the untreated acinus was sufficient to induce eversion. Analyses of acini revealed high curvature and low phosphorylated myosin in the apical cell surfaces relative to the basal surfaces. A vertex-based mathematical model that balances tension at cell-cell interfaces revealed a fivefold greater basal cell surface tension relative to the apical cell surface tension. The model suggests that the difference in surface energy between the apical and basal surfaces is the driving force for acinar eversion. Our findings raise the possibility that a loss of mechanical homeostasis may cause apical-out polarity states in human cancers.
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DOI：
10.1083/jcb.201009001
发表时间：
2011-04-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Francis SS;Sfakianos J;Lo B;Mellman I
通讯作者：
Mellman I
影响因子：
3.9
作者：
Manning, Lawton;Holmes, Julia;Vidi, Pierre-Alexandre
通讯作者：
Vidi, Pierre-Alexandre
影响因子：
50.3
作者：
Paszek, MJ;Zahir, N;Weaver, VM
通讯作者：
Weaver, VM
影响因子：
3.3
作者：
Yu, Wei;Fang, Xiaohui;Mostov, Keith
通讯作者：
Mostov, Keith
影响因子：
3.4
作者：
Misra, Mahim;Audoly, Basile;Shvartsman, Stanislav Y.
通讯作者：
Shvartsman, Stanislav Y.