Smooth muscle tension induces invasive remodeling of the zebrafish intestine.
Smooth muscle tension induces invasive remodeling of the zebrafish intestine.
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DOI：
10.1371/journal.pbio.1001386
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发表时间：
2012
期刊：
影响因子：
9.8
通讯作者：
Pack M
中科院分区：
文献类型：
--
作者：
Seiler C;Davuluri G;Abrams J;Byfield FJ;Janmey PA;Pack M
斑马鱼的遗传分析发现了一种新的物理信号机制，可驱动侵袭伪足样结构的形成并促进体内细胞侵袭。启动细胞侵袭的信号尚不清楚，但越来越多的证据表明细胞外物理信号发挥着重要作用。在这里，我们发现斑马鱼熔断（mlt）突变体肠道上皮细胞的入侵是由于周围平滑肌细胞层不受调节的收缩张力而产生的。 MLT 中的物理信号驱动上皮内膜突起的形成，类似于侵袭性伪足，即侵袭性癌细胞中存在的基质降解突起。 Tks5（一种哺乳动物细胞中侵袭伪足形成所需的 Src 底物）的敲除可阻止突起的形成并挽救 mlt 中的侵袭。 Src信号的激活在野生型上皮细胞中诱导了类似侵袭伪足的突起，但是这些细胞没有迁移到组织基质中，因此表明在该体内模型中，突起是入侵所必需的，但不足以进行侵袭。转录谱实验表明，MLT 幼虫中对活性氧 (ROS) 敏感的基因上调。 ROS 发生器在杂合性 mlt 幼虫中诱导入侵伪足样突起和入侵，但对野生型幼虫没有影响。致癌 Ras 和 Wnt 信号的共同激活增强了 mlt 杂合子对 ROS 发生器的反应性。这些发现首次提供了证明侵袭伪足在体内组织细胞侵袭中发挥作用的直接证据。此外，他们还发现了一种对氧化还原和致癌信号敏感的可诱导物理信号传导途径，可以驱动这一过程。消化道内衬的上皮细胞通过一层薄薄的细胞外基质（称为基底膜）与结缔组织基质分开。在细胞侵袭期间，如在癌症转移期间发生的那样，上皮细胞突破基底膜并侵入组织基质。侵入细胞在体外降解基底膜所用的蛋白酶位于称为侵入伪足的特殊质膜突起中。然而，目前尚不清楚侵袭伪足是否是体内细胞侵袭所必需的，或者是什么触发了它们的形成。在这里，我们发现，斑马鱼突变体熔解肠道中的上皮细胞形成侵入伪足样突起，并侵入组织基质，以响应周围平滑肌层不受调节的收缩张力。在该体内模型中，响应于这种物理信号而形成的侵袭伪足样突起是上皮细胞侵袭所必需的，并且当氧化应激诱导不受调节的平滑肌收缩时，可以诱导它们。这些发现提供了第一个直接证据，证明侵袭伪足在体内组织细胞侵袭中发挥作用，并确定了一种可以驱动这一过程的新型诱导物理信号传导机制。
Genetic analyses in zebrafish identify a novel physical signaling mechanism that drives formation of invadopodia-like structures and promotes cell invasion in vivo. The signals that initiate cell invasion are not well understood, but there is increasing evidence that extracellular physical signals play an important role. Here we show that epithelial cell invasion in the intestine of zebrafish meltdown (mlt) mutants arises in response to unregulated contractile tone in the surrounding smooth muscle cell layer. Physical signaling in mlt drives formation of membrane protrusions within the epithelium that resemble invadopodia, matrix-degrading protrusions present in invasive cancer cells. Knockdown of Tks5, a Src substrate that is required for invadopodia formation in mammalian cells blocked formation of the protrusions and rescued invasion in mlt. Activation of Src-signaling induced invadopodia-like protrusions in wild type epithelial cells, however the cells did not migrate into the tissue stroma, thus indicating that the protrusions were required but not sufficient for invasion in this in vivo model. Transcriptional profiling experiments showed that genes responsive to reactive oxygen species (ROS) were upregulated in mlt larvae. ROS generators induced invadopodia-like protrusions and invasion in heterozygous mlt larvae but had no effect in wild type larvae. Co-activation of oncogenic Ras and Wnt signaling enhanced the responsiveness of mlt heterozygotes to the ROS generators. These findings present the first direct evidence that invadopodia play a role in tissue cell invasion in vivo. In addition, they identify an inducible physical signaling pathway sensitive to redox and oncogenic signaling that can drive this process. The epithelial cells lining the digestive tract are separated from the connective tissue stroma by a thin layer of extracellular matrix called the basement membrane. During cell invasion, as occurs during cancer metastasis, epithelial cells breach the basement membrane and invade the tissue stroma. The proteases used by invasive cells to degrade basement membrane in vitro are localized in specialized plasma membrane protrusions known as invadopodia. It is not known, however, whether invadopodia are required for cell invasion in vivo or what triggers their formation. Here, we show that epithelial cells in the intestine of the zebrafish mutant meltdown form invadopodia-like protrusions and invade the tissue stroma in response to unregulated contractile tone in the surrounding smooth muscle layer. The invadopodia-like protrusions that form in response to this physical signal are required for epithelial cell invasion in this in vivo model, and they can be induced when unregulated smooth muscle contraction is induced by oxidative stress. These findings provide the first direct evidence that invadopodia play a role in tissue cell invasion in vivo and identify a novel inducible physical signaling mechanism that can drive this process.
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DOI：
10.1073/pnas.0801213105
发表时间：
2008-04-08
影响因子：
11.1
作者：
Alhopuro, Pia;Phichith, Denis;Aaltonen, Lauri A.
通讯作者：
Aaltonen, Lauri A.
影响因子：
6.6
作者：
Blouw, Barbara;Seals, Darren F.;Courtneidge, Sara A.
通讯作者：
Courtneidge, Sara A.
影响因子：
3.5
作者：
Abrams J;Davuluri G;Seiler C;Pack M
通讯作者：
Pack M
影响因子：
3.7
作者：
Crimaldi, Luca;Courtneidge, Sara A.;Gimona, Mario
通讯作者：
Gimona, Mario
影响因子：
--
作者：
CHEN, WT
通讯作者：
CHEN, WT