New tools for understanding metastasis through tissue resident cells: enabling an Extensive Medicine strategy for metastatic disease

项目摘要 癌症仍然是一个威胁，因为我们无法解决转移性疾病。肿瘤转移是 癌细胞和被侵入组织的微环境之间相互作用的悠久历史， 患者内和患者间高度异质性的疾病。因此，目前可用的治疗方法 对于转移性疾病显示有限的功效，因为大部分肿瘤发展逃避策略。 因此，针对一种新型癌症的共性可能会为相当一部分人带来新的治疗方法。 转移性患者。世纪以来，人们已经认识到，侵入的组织（"土壤"） 在转移中与转移性细胞（"种子"）一样重要。然而，技术限制使大多数人 研究的重点是"种子"的主要疾病或内在特性。然而，移植器官并不是 被动的;它们含有复杂的细胞类型，这些细胞类型必须与入侵细胞相互作用以允许入侵， 扩张.我提出了一个新的概念框架，在这个框架中， 驻留细胞（MiRC）是转移的一般特征，并且可以用作新的治疗靶点。因此 改变可能在癌症类型和患者中很常见，靶向它们可能会导致广泛医学 补充精准医疗的方法。为了实现这一愿景，一种新的体内标记和跟踪策略 需要转移性细胞和MiRC之间的相互作用。我们开发了这样一个系统，基于 合成Notch（SynNotch）受体。我们使用了这款新的SynNotch MiRC贴标系统， 肝脏生物学专业知识（肝脏是癌症类型中最常见的转移部位）， 分离转移相互作用肝细胞（MiH）。通过使用这种方法，我们的第一个目标是识别 在多种鼠和人肝转移模型中MiH的分子改变;候选基因将 测试减少转移的能力。此外，为了充分发挥这一新颖概念的潜力， 框架，我们将生成一个遗传工具箱，以允许分析任何转移模型中的任何MiRC。最后， 我们将逆转SynNotch系统，以追踪与组织驻留细胞相互作用的转移细胞， 选择;这将有助于解决问题，如转移性进展是否发生顺序或通过 从原发肿瘤发展，以及淋巴结浸润是否是转移的先决条件。这 该提案旨在为解决转移性肿瘤的新方法提供概念和实验基础。 基于使用我们的新SynNotch体内系统的MiRC的分子表征来治疗疾病。工具和 这里建立的技术也可以应用于转移细胞，以帮助解决基本问题， 关于转移过程最后，这些相同的工具和技术可以用于其他疾病， 涉及特定细胞间相互作用的生物过程。

Project Summary Cancer remains a menace because of our inability to tackle metastatic disease. Metastasis is the culmination of a long history of interactions between cancer cells and the microenvironments of invaded tissues, resulting in a disease that is highly heterogeneous intra- and interpatient. For this reason, the currently available treatments for metastatic disease show limited efficacy since a large fraction of tumors develop escape strategies. Therefore, targeting a new type of cancer commonality could lead to new treatments for a significant portion of metastatic patients. It has been recognized for more than a century that the invaded tissue (“soil”) plays a role in metastasis as important as that of the metastatic cells (“seed”). However, technical limitations have kept most research focused on the primary disease or intrinsic properties of the “seed”. Yet colonized organs are not passive; they contain complex sets of cell types which must interact with invading cells to allow invasion and expansion. I propose a new conceptual framework in which molecular changes arising in metastasis-interacting resident cells (MiRCs) are a general feature of metastasis and could serve as new therapeutic targets. As such alterations may be common across cancer types and patients, targeting them could lead to Extensive Medicine approaches to complement Precision Medicine. To fulfill this vision, a new in vivo strategy to label and track interactions between metastatic cells and MiRCs is required. We have developed such a system, based on synthetic Notch (SynNotch) receptors. We have used this new SynNotch MiRC Labeling System, and our expertise in liver biology (the liver is the most common site of metastasis across cancer types), to label and isolate metastasis-interacting hepatocytes (MiHs). By using this approach, our first goal is to identify the molecular alterations in MiHs across multiple murine and human liver metastatic models; candidate genes will be tested for ability to reduce metastasis. In addition, to realize the full potential of this novel conceptual framework, we will generate a genetic toolbox to allow the analysis of any MiRC in any metastatic model. Finally, we will invert the SynNotch System to track metastatic cells which have interacted with a tissue resident cell of choice; this will help address questions such as whether metastatic progression occurs sequentially or by developing from the primary tumor, and whether invasion of lymph nodes is a prerequisite for metastasis. This proposal aims to provide the conceptual and experimental foundation for a new approach to tackle metastatic disease based on the molecular characterization of MiRCs using our new SynNotch in vivo System. Tools and techniques established here can also be applied in metastatic cells to aid in resolving fundamental questions about the metastatic process. Finally, these same tools and techniques can be used in other diseases or biological processes involving specific cell-cell interactions.