Plasticity of epithelial cell boundaries governed by EGF and actin remodelling

上皮细胞边界的可塑性受 EGF 和肌动蛋白重塑控制

• 批准号: BB/M003434/1
• 负责人: Sylvie Urbe
• 金额: $ 47.92万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM003434%2F1
• 关键词: Plasticity; epithelial; cell; boundaries; governed

The tissue cells in our body respond to circulating factors, amongst them so-called growth factors, by undergoing changes in shape, movement or division rates. One of the most important growth factors is called EGF and it binds to its own receptor to convey the instructions necessary for these changes to the interior of the cell. In some cancer types, this receptor can be altered such that it continuously demands these types of changes from the cell; i.e. it forces the cell to grow and divide abnormally, extract itself from the tissue boundaries and move to another site. It follows that drugs, which inhibit this receptor are of widespread interest and a major focus of pharmaceutical companies.We have studied normal, non-cancerous breast cells that can routinely be grown in petri dishes in the presence of growth factors including EGF. These breast cells form a continuous sheet, but within this sheet, cells remain able to roam around. However when we remove the EGF, these cells project long, finger-like protrusions into each other, which we call "interdigitations". In these interdigitated sheets, cell positions are fixed like the pieces of a completed jigsaw puzzle. If we add fresh EGF to this mesh of interdigitated cells, the finger-like protrusions disappear and the cells start to move around again. Such interdigitations are in fact common in tissues that have to endure mechanical stress. They may help to give the tissue superior flexibility and strength to withstand, for example, changes in volume in breast tissue due to lactation. Our work has defined an experimental set-up in which we can study the proteins that respond to the EGF receptor and mediate this reversible remodeling process. New insights that will be gained from this work may help to inform both on the mechanism by which normal tissues increase their strength but also on disease states in which tissue boundaries are compromised due to a deregulation of the proteins involved.

我们体内的组织细胞对循环因子做出反应，其中包括所谓的生长因子，通过改变形状，运动或分裂速率。其中最重要的生长因子之一是EGF，它与自己的受体结合，将这些变化所需的指令传达到细胞内部。在某些癌症类型中，这种受体可以被改变，使得它不断地要求细胞发生这些类型的变化;即它迫使细胞异常生长和分裂，将自己从组织边界中提取出来并移动到另一个部位。因此，抑制这种受体的药物引起了广泛的兴趣，也是制药公司的主要关注点。我们研究了正常的、非癌性的乳腺细胞，这些细胞可以在培养皿中常规地在生长因子（包括EGF）的存在下生长。这些乳腺细胞形成一个连续的薄片，但在这个薄片中，细胞仍然能够四处漫游。然而，当我们去除EGF时，这些细胞会相互投射出长的手指状突起，我们称之为“交错”。在这些相互交叉的薄片中，细胞的位置就像一个完整的拼图一样固定。如果我们将新鲜的EGF添加到这个交错的细胞网格中，手指状突起消失，细胞又开始移动。事实上，这种交错在必须承受机械应力的组织中很常见。它们可以帮助给予组织上级柔性和强度以承受例如由于哺乳引起的乳房组织体积的变化。我们的工作已经确定了一个实验装置，在其中我们可以研究对EGF受体产生反应并介导这种可逆重塑过程的蛋白质。从这项工作中获得的新见解可能有助于了解正常组织增加其强度的机制，以及由于相关蛋白质的失调而损害组织边界的疾病状态。