Defining the First Hours of Lung metastasis using Intravital Live-Imaging

描述（由申请人提供）：据信肺是某些转移性肿瘤播种的容许器官。最近的研究支持了这一点，发现远端原发性肿瘤促使骨髓源性细胞（BMDC）迁移到肺中，形成转移前小生境（PreMN），并且这些细胞对于稳健和有效的转移至关重要。这些研究使人们越来越认识到免疫系统和肺前MN在肺转移中的重要性，但许多重要问题仍然存在，迄今为止尚未解决。最值得注意的是，还没有直接的方法来评估DTC在肺PreMN内与正常的“较不允许的”肺组织内的行为和命运。此外，PreMN包含一组不同的免疫细胞，与这些群体的相互作用对DTC存活的影响尚不清楚。为了了解和治疗肺转移，我们必须首先解决这些关键问题，在体内 这项R21探索性资助的基础是应用新的实时活体成像方法来了解肺部如何处理传入细胞。特别相关的是要了解为什么以及如何转移细胞在环境中生存，以及宿主细胞如何“接收”它们并保护它们免受血管系统细胞的正常消除。我们假设从微血管系统中正常去除细胞是一个修复过程，转移细胞在宿主细胞的帮助下延长持续时间以实现成功定植。 该项目的整体成功将由我们对转移细胞到达肺部后所面临的时空景观的了解来定义。是肿瘤细胞接种后被“辅助”宿主细胞加入，还是成功的转移直接被这些细胞捕获？相对于巨噬细胞和骨髓源性细胞的募集，进入的转移细胞的增殖动力学是什么？持续的损伤修复以何种方式加速了这一过程？更好地理解这一点，沿着研究方法的发展，将允许更合理的方法来阻断肿瘤转移。

DESCRIPTION (provided by applicant): It is believed that the lung is a permissive organ for the seeding of certain metastasizing tumors. Recent studies have supported this, finding that distal primary tumors instigate bone marrow-derived cell (BMDC) migration into the lung, forming a pre-metastatic niche (PreMN), and that these cells are crucial for robust and efficient metastasis. These studies have led to a growing recognition of the importance of the immune system and the pulmonary PreMN in lung metastasis, but many important questions remain and have been hitherto inaccessible. Most notably, there has been no direct way of assessing the behavior and fate of DTCs within the lung PreMN versus normal 'less-permissive' lung tissue. Further, the PreMN contains a diverse set of immune cells and the effect of interaction with these populations on DTC survival is unknown. In order to understand and therapeutically target pulmonary metastasis we must first address these crucial questions, in vivo The basis for this R21 exploratory grant is to apply novel real-time intravital imaging approaches to understand how the lung deals with incoming cells. Of particular relevance are to understand why and how metastatic cells survive in the environment and how host-cells 'receive' them and protect them from normal elimination of cells from the vasculature. We hypothesize that normal removal of cells from microvasculature is a repair process which metastatic cells, helped by host cells, extend in duration to achieve successful colonization. The overall success of this project will be defined by our knowledge of the spatiotemporal landscape that metastatic cells face upon their arrival in the lung. Are tumor cells seeded followed by being joined by 'helper' host cells or are successful mets captured directly by these cells? What are the kinetics of the proliferation of incoming metastatic cells relative to the recruitment of macrophages and bone-marrow derived cells? In what way is this process accelerated by ongoing damage repair? Better understanding of this, along with the development of a method to study it, will permit much more rational approaches toward blocking tumor metastasis.