Spatiotemporal Control of Tumor Cell Signaling

描述(申请人提供)：转移，癌细胞从原发肿瘤扩散到远处，通过单个细胞与肿瘤分离，随后侵入血管内皮细胞，进入血流，最终在继发部位插入和生长。在血流中循环的生长因子从亲代部位召唤肿瘤细胞，这是一个固有的空间驱动过程。信号通路已经进化，细胞可以对其环境做出反应，其中许多通路也具有明显的时空特性。简而言之，对环境刺激的生化反应的经典观点，即一系列酶催化的线性反应，并不总是充分解释细胞的潜在行为。事实上，现在出现的关于细胞信号传递的观点认为，细胞行为不仅取决于激活哪条途径，还取决于何时、何地以及哪些其他途径被激活。将构建一系列波长不同的光激活信号蛋白，以探索空间定位的蛋白质活性对细胞内生化和细胞范围迁移的影响。此外，这些共价修饰的蛋白质结构将被用来检验作为时间和空间函数的多个信号通路对迁移能力的协同影响。最后，我们将讨论一个新兴的转移潜能模型的有效性。 公共卫生相关性：这项研究计划的首要目标是描绘驱动早期转移阶段的信号通路所起的时空作用。侵袭潜能的潜在机制的阐明最终可能成为治疗转移性疾病的新的治疗策略的基础。

DESCRIPTION (provided by applicant): Metastasis, the spread of cancer cells from a primary tumor to distant sites, proceeds via separation of individual cells from the tumor, subsequent invasion into the endothelium, entry into the bloodstream, and eventual insertion and growth at a secondary site. Growth factors circulating through the bloodstream beckon tumor cells from the parental site, an inherently spatially driven process. Signaling pathways have evolved so that cells can respond to their environment and many of these pathways possess pronounced spatiotemporal properties as well. In short, the classic view of a biochemical response to an environmental stimulus, namely a linear series of enzyme catalyzed reactions, does not always adequately explain the underlying behavior of cells. Indeed, the now emerging view of cell signaling posits that cell behavior is not only dependent upon which pathway is activated, but by when, where, and which other pathways are activated as well. A series of wavelength-distinct light-activatable signaling proteins will be constructed to explore the intracellular biochemical and cell wide migratory consequences of spatially localized protein activity. In addition, these covalently modified protein constructs will be used to examine the synergistic influence of multiple signaling pathways as a function of time and space on migratory aptitude. Finally, we will address the validity of an emerging model of metastatic potential. PUBLIC HEALTH RELEVANCE: The overriding goal of this research program is to delineate the spatiotemporal role played by signaling pathways that drive the early stages of metastasis. Elucidation of the underlying mechanisms responsible for invasiveness potential could ultimately serve as the basis for new therapeutic strategies for the treatment of metastatic disease.