Technical Development Unit 1: Intelligent live imaging of metastasis patterns and subcellular molecular states at the whole organism level

项目摘要 荧光显微镜结合光学透明的斑马鱼异种移植模型具有潜力 以揭示癌细胞的功能异质性和适应性，这是其转移潜力的基础。 然而，这需要桥接不同的尺度，因为转移位点可以在整个生物体中形成， 需要以亚微米的3D分辨率成像。此外，特定的低占有率 转移小生境需要对许多异种移植物成像。这扩展了当前显微镜的能力 因为它们不能提供高通量、高空间分辨率和整个生物体成像 能力，同时。为了突破这一界限，我们将开发一种新的多模态显微镜， 以高通量方式在生物体和亚细胞尺度上自主成像。光遗传 模块还允许操纵路径或光转换选定的癌细胞，用于跟踪或 单细胞测序方法。计算管道将自动检测和选择循环 用于高分辨率成像的许多异种移植物的转移部位。这将首次允许 功能状态的定量比较，如形态、存活和增殖，以及信号传导 在不同的壁龛之间。我们预计，多模态显微镜和计算的结合， 自主成像的管道将为癌症功能异质性的关键方面提供新的见解 转移

Project Summary Fluorescence microscopy combined with the optically transparent Zebrafish xenograft model has the potential to unravel the functional heterogeneity and adaptation of cancer cells that underlies their metastatic potential. However, this requires bridging disparate scales, as metastatic sites can form across an entire organism, and cancer cells within need to be imaged with sub-micron 3D resolution. Further, low occupancy of specific metastatic niches requires imaging many xenografts. This stretches the capabilities of current microscope technology as they fail to provide high-throughput, high-spatial resolution, and whole organism imaging capability at the same time. To break through this boundary, we will develop a new multi-modal microscope to autonomously image both at the organism and subcellular scale in a high-throughput fashion. An optogenetic module further allows to manipulate pathways or photo-convert selected cancer cells for either tracking or single cell sequencing approaches. A computational pipeline will automatically detect and select recurring metastatic sites across many xenografts for high-resolution imaging. This will allow for the first time the quantitative comparison of functional states such as morphology, survival and proliferation, and signaling between different niches. We anticipate that the combination of multi-modal microscopy and the computational pipelines for autonomous imaging will shed new light on key aspects of functional heterogeneity in cancer metastasis.