Department of Oncology and Pathology, U2, Bioclinicum J6:20, Solnavägen 30 Karolinska Institutet, Solna, 171 64 Stockholm, Sweden.
Department of Physics, Faculty of Science: 2 Science Drive 3, S7-01-10, Lower Kent Ridge Road, Singapore 117542, Singapore.
Cells. 2023 Jun 21;12(13):1682. doi: 10.3390/cells12131682.
The spread of tumor cells and the formation of distant metastasis remain the main causes of mortality in cancer patients. However, the mechanisms governing the release of cells from micro-environmental constraints remain unclear. E-cadherin negatively controls the invasion of epithelial cells by maintaining cell-cell contacts. Furthermore, the inactivation of E-cadherin triggers invasion in vitro. However, the role of E-cadherin is complex, as metastasizing cells maintain E-cadherin expression, which appears to have a positive role in the survival of tumor cells. In this report, we present a novel mechanism delineating how E-cadherin function is modulated to promote invasion. We have previously shown that E-cadherin is associated with p100AmotL2, which is required for radial actin formation and the transmission of mechanical force. Here, we present evidence that p60AmotL2, which is expressed in invading tumor cells, binds to the p100AmotL2 isoform and uncouples the mechanical constraint of radial actin filaments. We show for the first time that the coupling of E-cadherin to the actin cytoskeleton via p100AmotL2 is directly connected to the nuclear membrane. The expression of p60AmotL2 inactivates this connection and alters the properties of the nuclear lamina, potentiating the invasion of cells into micropores of the extracellular matrix. In summary, we propose that the balance of the two AmotL2 isoforms is important in the modulation of E-cadherin function and that an imbalance of this axis promotes ameboid cell invasion.
肿瘤细胞的扩散和远处转移的形成仍然是癌症患者死亡的主要原因。然而，控制细胞脱离微环境限制的机制仍不清楚。E-钙黏蛋白通过维持细胞-细胞接触来负调控上皮细胞的侵袭。此外，E-钙黏蛋白的失活会触发体外侵袭。然而，E-钙黏蛋白的作用是复杂的，因为转移细胞保持 E-钙黏蛋白的表达，这似乎对肿瘤细胞的存活有积极作用。在本报告中，我们提出了一种新的机制，阐明了 E-钙黏蛋白功能如何被调节以促进侵袭。我们之前已经表明，E-钙黏蛋白与 p100AmotL2 相关，p100AmotL2 是放射状肌动蛋白形成和机械力传递所必需的。在这里，我们提供的证据表明，表达于侵袭性肿瘤细胞中的 p60AmotL2 与 p100AmotL2 亚型结合，并解除放射状肌动蛋白丝的机械约束。我们首次表明，E-钙黏蛋白通过 p100AmotL2 与肌动蛋白细胞骨架的偶联直接与核膜相连。p60AmotL2 的表达使这种连接失活，并改变核纤层的性质，从而增强细胞侵入细胞外基质微孔的能力。总之，我们提出两种 AmotL2 亚型的平衡对于 E-钙黏蛋白功能的调节很重要，而这种轴的失衡促进了阿米巴样细胞的侵袭。
