乳腺上皮组织形态发生的分子机制

Branching morphogenesis is a fundamental process essential for the formation of many vertebrate organs. However, our understanding of the cellular and molecular basis of this developmental process has remained largely unclear, which has prevented the development of an effective strategy for treating various congenital defects and postnatal illnesses involving these organs. Recent studies, ours included, have shown that the fibroblast growth factor (FGF) signaling is essential for mammary gland development and its deregulation can lead to breast cancer. Our long-term goal is to understand the role of FGF signaling pathway in mammary stem cell biology and epithelial morphogenesis and how it is regulated at different stages to ensure normal development of the mammary gland. Here, we hypothesize that FGF receptor 1 and FGF receptor 2 regulate distinct aspect of epithelial morphogenesis in ductal elongation and collectively migration, respectively. Our hypothesis is based on our recent findings showing that FGF2 and FGF10 play differential roles in mammary gland branching and that FGF10 induces a novel phenomenon of directional migration of the stratified mammary epithelium. The specific aims are to: 1. Determine the role of FGF signaling in epithelial morphogenesis of the mammary gland. We have found that FGF10-FGFR2 signaling regulates the novel phenomenon of collective migration of stratified epithelium. We will determine whether FGF2-FGFR1 signaling regulates cell proliferation and ductal elongation. 2. Elucidate cell behavior during collective migration of stratified mammary epithelium. We will determine behavior of individual cells during collective migration so as to compare it with other known systems where leaders cell pulls the follower cells during migration. 3. Determine the molecular mechanism that regulates collective migration of mammary epithelium. Cytoskeletal organization, dynamics, and regulation are essential for directional migration of other single and collective cells. In this study, we will characterize the cytoskeletal organization and dynamics in migrating mammary epithelium and determine essential regulators that control this process.

分支的形态发生是脊椎动物器官形成过程中的一个重要步骤，但其机制至今仍不明了。研究表明成纤维细胞生长因子（FGF）信号通路对乳腺的正常发育极为重要，相反其去调控经常导致乳腺癌。我们的长期目标是阐明FGF信号通路及调控在乳腺干细胞生物学和上皮形态发生中的作用。在此，我们集中研究FGF受体1(FGFR1) 和2 (FGFR2)是否分别调控上皮形态发生中两个不同的侧面即导管延伸和集体迁移。该研究是基于我们的最新发现：即来源于同一配体家族的FGF2和FGF10功能各异而且后者能导致乳腺复层上皮定向迁移这个新颖的现象。我们的具体目标是：1）研究FGF信号在乳腺上皮形态发生中的作用。我们将确定FGF2-FGFR1信号通路是否调节上皮形态发生中的另一个侧面即细胞增殖和导管延伸；2）阐明乳腺复层上皮集体迁移过程中细胞行为；3）阐明乳腺上皮组织集体迁移的分子机制。

上皮在历史上一直被认为是不运动的组织，因为上皮细胞被认为是彼此束缚在一起的，其基质与它们的高表达粘附蛋白也被束缚在一起。 我们最近的工作首次表明脊椎动物上皮可以进行定向迁移，并且与所有其他已知的集体迁移模型相比，它使用一种新颖的机制来建立前后极性并进行功率迁移（Cell Reports，2020年）。 因此，我们的工作开辟了新的领域，以了解如何在脊椎动物上皮细胞中调节集体迁移以及如何劫持它以促进癌症转移。具体说来，集体迁移对于发育，伤口修复和癌症转移至关重要。对于大多数集合系统，“前导单元”既决定方向，又决定功率迁移。但是，尚不清楚高度极化的脊椎动物上皮在分支形态发生过程中如何定向迁移。我们在这里显示，与其他系统不同，乳腺上皮的前后极性是由响应FGF10梯度的前面优先细胞增殖建立的。这会导致额叶分层，两极基底极性丧失和前导细胞形成。前导细胞是动态种群，其向FGF10信号移动的速度比从动细胞更快，方向性更强，部分原因是其上皮内向信号的突出。在一起，我们的数据表明，乳腺上皮的定向迁移是一个独特的多步过程，并且尽管共享显着的细胞和分子相似性，但脊椎动物和无脊椎动物上皮分支是根本不同的过程。