Dynamic Organization of Cell Architecture in Multicellular Tissues

项目总结：多细胞组织中细胞结构的动态组织 大多数人类癌症起源于上皮组织。在癌症方面，进展 转移，这是肿瘤进展的终末期的特征，解释了 90%以上的死亡率。导致肿瘤细胞转移的事件已经被研究过了 通过对肿瘤细胞行为的研究，表明肿瘤的侵袭可以通过 集体细胞迁移。集体迁移的肿瘤细胞与单个细胞有许多相似之处 在发育过程中，迁移和动态重塑上皮组织。然而，虽然 单细胞迁移的信号机制已经得到了广泛的研究， 在动态重塑多细胞组织中协调细胞行为的机制是 不太为人所知。上皮细胞的组织重塑需要细胞极性的组织和 在组织平面内的行为，这一特性称为平面极性。早期的果蝇 胚胎是一种简单的多细胞上皮，其中蛋白质的平面极化定位 参与收缩和粘连导致组织经历戏剧性的形状变化 产生一个细长的头到尾的身体轴线。本项目的目标是剖析信令 建立平面极性和调节平面极化细胞的机制 在这个动态重塑的组织中的重排。具体来说，这些研究将确定 将相邻细胞之间的相互作用转化为空间关系的分子途径 肌动蛋白细胞骨架组织的调节变化。在目标1中，我将执行损失和 获得功能研究，以确定涉及调节平面的关键信号通路 在轴延长过程中参与连接重塑的蛋白质的极化定位，与 重点研究调节肌动蛋白细胞骨架的组织和动态的蛋白质。在……里面 目标2，我将研究这些过程是如何由本地提供的细胞外线索来调节的 细胞间的相互作用以定向和协调跨多细胞的肌动蛋白重组 人口。这些研究将揭示外部信号如何转化为平面极化 在上皮发育过程中细胞行为的变化，并将为深入了解 控制空间调节的组织和重塑的基本机制 肌动蛋白在多细胞组织中的细胞骨架。洞察细胞行为的调节和 肌动球蛋白在体内的动力学有助于阐明控制集体细胞的机制 在其他情况下的行为，例如在上皮性肿瘤的侵袭和转移期间。

PROJECT SUMMARY: Dynamic Organization of Cell Architecture in Multicellular Tissues The majority of human cancers are derived from epithelial tissues. In carcinomas, advancement to metastasis, which is characteristic of the terminal stages of tumor progression, accounts for over 90% of mortality. The events that lead to tumor cell metastasis have been investigated through studies of tumor cell behavior, which suggest that tumor invasion can initiate through collective cell migration. Collectively migrating tumor cells share many similarities with single cell migration and with dynamically remodeling epithelial tissues during development. However, while the signaling mechanisms underlying single cell migration have been extensively studied, the mechanisms that coordinate cell behaviors in dynamically remodeling multicellular tissues are less well understood. Tissue remodeling in epithelia requires the organization of cell polarity and behavior in the plane of the tissue, a property referred to as planar polarity. The early Drosophila embryo is a simple multicellular epithelium in which the planar polarized localization of proteins involved in contraction and adhesion cause the tissue to undergo dramatic changes in shape to produce an elongated head-to-tail body axis. The goal of this project is to dissect the signaling mechanisms involved in establishing planar polarity and regulating planar polarized cell rearrangements in this dynamically remodeling tissue. Specifically, these studies will determine the molecular pathways that translate interactions between neighboring cells into spatially regulated changes in the organization of the actin cytoskeleton. In Aim 1, I will perform loss and gain of function studies in order to identify key signaling pathways involved in regulating the planar polarized localization of proteins involved in junctional remodeling during axis elongation, with a focus on proteins that regulate the organization and dynamics of the actomyosin cytoskeleton. In Aim 2, I will study how these processes are regulated by extracellular cues provided by local interactions between cells to orient and coordinate actin reorganization across a multicellular population. These studies will reveal how external signals are translated into planar polarized changes in cell behavior during epithelial development and will provide insight into the fundamental mechanisms that control the spatially regulated organization and remodeling of the actin cytoskeleton in a multicellular tissue. Insight into the regulation of cell behavior and actomyosin dynamics in vivo can help to elucidate the mechanisms that control collective cell behavior in other contexts, such as during the invasion and metastasis of epithelial tumors.