细胞侦测侵袭信号的新方式——膜受体“聚集-消散”动态行为的形成机制研究

Cell invasion begins with cell detecting and responding to extracellular invasive signals. However, the mechanisms underlying this detection and response remain elusive, largely because cancer invasion often occurs in deep tissues that are inaccessible for real-time visualization and analysis. Thus, we choose to study C. elegans anchor cell invasion, as it highly resembles cancer cells’ invasive behavior. We have established the confocal live-cell imaging technique at a single cell resolution. Using this model, we have previously discovered a novel invasive signal detection mechanism that is characterized by the periodic assembly-disassembly of a transmembrane receptor on the cell plasma membrane. We have revealed the functional roles of this behavior in detecting and locating an invasive signal. This proposal is focused on decoding the formation mechanism underpinning this assembly-disassembly of a transmembrane receptor. With the help of the techniques of imaging, cell biology and genetics, we will analyze the photodynamics of this periodic behavior, reveal vesicular pathways underlying this periodic clustering, and identify the genes that regulate this dynamic behavior. This project will help deepen the understanding of how cells initiate invasion, and may provide valuable information for blocking cancer cell invasion at the early stage.

肿瘤侵袭转移起始于细胞侦测外界侵袭转移信号，但该侦测机制不清。原因之一是肿瘤侵袭常发生在深部组织，难以实时动态观察和分析。为此，我们选择与肿瘤侵袭行为相似的线虫锚定细胞侵袭过程作为研究模型，建立了转盘共聚焦显微镜-活体单细胞原位实时成像技术。利用该模型，申请人前期工作发现了一种基于膜受体周期性“聚集-消散”行为的全新侵袭信号侦测方式，揭示了该行为的自动搜寻、靶向定位侵袭信号的功能 。本课题旨在进一步阐释膜受体“聚集-消散” 行为的形成机制。我们将结合显微成像技术，细胞生物学和遗传学等方法分析该行为的细胞动力学特征，揭示实现该行为的细胞生物学途径，明确聚集和消散过程的主要调节因子及调控机制，以深入理解侵袭转移机理，为阻断肿瘤转移提供新思路。

肿瘤侵袭转移起始于细胞侦测外界侵袭转移信号，但该侦测机制不清。我们选择与肿瘤侵袭行为相似的线虫锚定细胞侵袭过程作为研究模型，建立了转盘共聚焦显微镜-活体单细胞原位实时成像技术。利用该模型，我们的前期工作发现了一种基于膜受体周期性“聚集-消散”行为的全新侵袭信号侦测方式，揭示了该行为的自动搜寻、靶向定位侵袭信号的功能。本课题旨在进一步阐释膜受体周期性“聚集-消散”行为的形成机制。利用单细胞活体原位实时动态显微成像和分析技术，我们发现自主激活的膜受体UNC-40在细胞膜上随机区域周期性“聚集-消散”。UNC-34和微丝调节基因调控UNC-40的聚集。囊泡参与UNC-40的转运，调节UNC-40在细胞膜上的“聚集-消散”。madd-2基因调控UNC-40的消散。我们的研究揭示了膜受体“聚集-消散”的细胞生物学途径，明确了聚集和消散过程的主要调节因子及调控机制，进一步深入理解侵袭转移机理，为阻断肿瘤转移提供新思路。