Spatial Patterning in the Progressing Tumor - The Role of Notch

当肿瘤细胞移动并开始扩散到患者全身时，癌症就会变得致命。为了变得能动，细胞必须经历其组成和行为的根本性变化，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类型的稳定命运过渡到另一种类型时，这些根本性的变化就会出现。该项目详细介绍了一项理论-实验-物理-生物学的联合努力，以研究EMT是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的。这里特别关注的是Notch信号通路。这一途径因其在发育生物学中的作用而被广泛研究，并间接与癌症有关，但从未在这方面进行过系统的研究。要研究的假设是，这一途径可以允许一起接受EMT的小细胞簇的形成，然后这些细胞作为一个集体在建立继发性肿瘤的过程中传播。如果被证明是真的，这些想法将阐明转移的根本来源，并可能在未来为预后和治疗提供新的策略。细胞间的相互作用，无论是肿瘤细胞之间的相互作用，还是肿瘤与基质细胞之间的相互作用，都被认为是许多实体肿瘤的关键组成部分。研究人员将重点研究Notch途径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。要做到这一点，需要使用和扩展非平衡模式形成领域的复杂理论技术，并结合专注于胰腺癌细胞株的实验计划，在体外条件下进行2D和3D研究，既没有支持癌症相关的成纤维细胞，也有支持癌症相关的成纤维细胞。特别重要的是测量EMT状态(和其他已知相关性)的空间相关性，并根据不同的信号假设将这些与预期进行比较。用越来越现实的模型建立和模型求解迭代这些实验，将允许为肿瘤的集体行为创建一个定量可靠的图像，远远超出目前的单个细胞方法。该项目由物理部的生命系统物理计划和NSF的分子和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.