Spatiotemporal Control of Tumor Cell Signaling

描述（由申请人提供）：转移，即癌细胞从原发性肿瘤扩散到远处部位，通过将单个细胞从肿瘤分离，随后侵入内皮，进入血流，并最终在继发部位插入和生长而进行。通过血流循环的生长因子从母体部位召唤肿瘤细胞，这是一个内在的空间驱动过程。信号通路已经进化，使得细胞可以对它们的环境做出反应，并且这些通路中的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，即酶催化反应的线性系列，并不总是充分解释细胞的基本行为。事实上，现在出现的细胞信号转导观点认为，细胞行为不仅取决于哪条通路被激活，而且还取决于何时、何地以及其他哪些通路被激活。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的细胞内生化和细胞范围内的迁移后果。此外，这些共价修饰的蛋白质构建体将被用来检查作为迁移能力的时间和空间的函数的多个信号传导途径的协同影响。最后，我们将讨论一个新的转移潜力模型的有效性。 公共卫生相关性：这项研究计划的首要目标是描绘时空的作用所发挥的信号通路，推动早期阶段的转移。阐明潜在的侵袭性机制，最终可以作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.