Spatial Patterning in the Progressing Tumor - The Role of Notch

当肿瘤细胞变得能动并开始扩散到患者全身时，癌症就变得致命。 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稳定的命运过渡到另一种稳定的命运时，这些根本性的变化就会出现。该项目详细介绍了一个联合的理论-实验物理学-生物学努力，研究如何通过肿瘤细胞之间传递的化学信号在空间和时间上协调EMT。 这里的具体重点是Notch信号通路。这一通路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，但从未在此背景下进行过系统研究。待研究的假设是，该途径可以允许一起经历EMT的小细胞簇的形成，并且随后作为集体行进到建立继发性肿瘤的途中。如果被证明是正确的，这些想法将揭示转移的根本起源，并可能在未来提供新的预后和治疗策略。细胞-细胞相互作用，包括肿瘤细胞之间以及肿瘤细胞和基质细胞之间的相互作用，已知是许多实体瘤的关键组成部分。研究人员将专注于这些相互作用之一，即Notch途径介导的相互作用，如何协调细胞表型，从而控制肿瘤进展。为了实现这一点，将需要使用和扩展的复杂的理论技术，从该领域的非平衡模式的形成耦合到一个实验计划集中在胰腺癌细胞系进行研究，在2D和3D的体外条件下，无论是没有和支持癌症相关的成纤维细胞。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），并将这些与基于不同信令假设的预期进行比较。迭代这些实验与越来越逼真的模型建立和模型求解将允许创建一个定量可靠的图片的集体行为的肿瘤，远远超出目前的单个细胞的approaches.This项目是共同资助的物理学生活系统计划在物理部和分子和细胞生物科学部在NSF。

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.