Spatial Patterning in the Progressing Tumor - The Role of Notch

当肿瘤细胞变得活跃并开始扩散到病人全身时，癌症就变得致命了。为了变得有运动能力，细胞必须经历其组成和行为的根本改变，即所谓的上皮-间充质转化（EMT）。当控制细胞状态的基因网络从一种稳定的命运转变为另一种稳定的命运时，这些根本性的变化就出现了。该项目详细介绍了一项理论-实验-物理-生物学联合努力，以研究EMT如何通过在肿瘤细胞之间传递的化学信号在空间和时间上协调。这里的重点是Notch信号通路。该途径在发育生物学中的作用已被广泛研究，并间接涉及癌症，但从未在此背景下进行系统研究。要研究的假设是，这一途径可以允许形成一起经历EMT的小细胞簇，然后作为一个集体在继发性肿瘤的建立过程中行进。如果被证明是正确的，这些想法将阐明转移的基本起源，并可能在未来为预后和治疗提供新的策略。细胞与细胞之间的相互作用，包括肿瘤细胞本身和肿瘤与基质细胞之间的相互作用，是许多实体瘤的关键组成部分。研究人员将重点关注Notch通路介导的其中一种相互作用如何协调细胞表型，从而控制肿瘤进展。为了实现这一目标，将需要使用和扩展来自非平衡模式形成领域的复杂理论技术，并将其与一个专注于胰腺癌细胞系的实验计划结合起来，在体外条件下进行二维和三维的研究，无论是否支持癌症相关成纤维细胞。特别重要的是测量EMT状态的空间相关性（以及其他已知的相关性），并将其与基于不同信号假设的预期进行比较。通过越来越现实的模型构建和模型求解来重复这些实验，将允许为肿瘤的集体行为创建一个定量可靠的图像，远远超出当前的单个细胞方法。该项目由美国国家科学基金会物理部生命系统物理项目和分子与细胞生物科学部共同资助。

Cancer becomes deadly when tumor cells become motile and begin to spread throughout the patient's body. To become motile, cells must undergo radical changes in their composition and behavior, the so-called epithelial-mesenchymal transformation (EMT). These radical changes arise as the network of genes controlling the state of the cell transitions from one type of stable fate to another. This project details a joint theory-experiment physics-biology effort to study how EMT is coordinated in space and time by chemical signals passed among the tumor cells. The specific focus here is on the Notch signaling pathway. This pathway has been studied extensively for its role in developmental biology and has been implicated indirectly in cancer, but has never been studied systematically in this context. The hypothesis to be investigated is that this pathway can allow the formation of small clusters of cells that have undergone EMT together, and which thereafter travel as a collective en route to the establishment of a secondary tumor. If proven to be true, these ideas will shed light on the fundamental origins of metastasis and might in the future offer new strategies for both prognosis and treatment. Cell-cell interactions, both between tumor cells proper and between tumor and stromal cells, are known to be a key component of many solid tumors. The investigators will focus on how one of these interactions, that mediated by the Notch pathway, can coordinate cell phenotypes and can thereby control tumor progression. To accomplish this will require the use and extension of sophisticated theory techniques from the field of non-equilibrium pattern formation coupled to an experimental plan focused on pancreatic cancer cell lines to be studied in both 2d and 3d in vitro conditions, both without and with supporting cancer-associated fibroblasts. Of particular importance will be measuring spatial correlations of EMT state (and other known correlates) and comparing these to expectations based on different signaling assumptions. Iterating these experiments with increasingly realistic model-building and model-solving will allow for the creation of a quantitatively reliable picture for the collective behavior of the tumor, going well-beyond current individual cell approaches.This project is cofunded by the Physics of Living Systems Program in the Physics Division and the Molecular and Cellular Biosciences Division at NSF.