Tumor Microenvironment and Metastasis

项目概述（见说明）：肿瘤微环境和转移项目关注癌细胞与其微环境之间的相互作用，这些相互作用是肿瘤细胞侵袭周围组织、穿透血管并最终进入远处组织并生长的决定因素。研究旨在解读单核细胞、巨噬细胞、内皮细胞和癌细胞及其支持基质之间的信号传导途径和机械相互作用，这有助于转移表型。该项目的目标是：(1)剖析微环境在肿瘤进展和转移中的作用，特别是巨噬细胞亚群在肿瘤进展的各个阶段和要素中的贡献；2)阐明生长因子和细胞因子调控肿瘤细胞迁移、播散、血管生成和远处侵袭的分子机制；3)评估表面分子，如钙粘蛋白和膜表面寡糖在肿瘤进展中的作用；(4)表征参与肿瘤细胞和巨噬细胞运动的调节细胞骨架蛋白的分子的生化和结构特性，通过开发(i)体内调节细胞迁移的途径的活性状态的荧光生物传感器和（ii）用于定量长期跟踪原发肿瘤中不同的细胞群的光切换蛋白，以及(5)将这些发现转化为与人类相关的研究预测转移潜力和风险的组织，并确定治疗靶点。格鲁斯·里珀生物光子学中心开发了新的成像技术，为该项目提供了独特的工具，这些工具通过分析成像共享资源提供给更广泛的AECC社区。实验方法的本质是开发具有荧光标记细胞系的新型小鼠转基因模型。该项目成员的研究主要集中在乳腺癌上，尽管其他类型的肿瘤也得到了研究。本计划的研究部分由计划项目拨款支持，该拨款反映并进一步促进了该计划成员的合作研究。目前有来自11个部门的24名成员，其中10名是该项目的新成员，由22项NCI拨款（410万美元直接拨款）和18项其他同行评审的癌症相关拨款（350万美元直接拨款）支持。自上次CCSG审查以来，该计划成员发表了239篇与癌症相关的研究论文，其中23%为计划内出版物，28%为计划间出版物。

PROJECT SUMMARY (See instructions): The Tumor Microenvironment and Metastasis Program focuses on the interactions between cancer cells and their microenvironment that are determinants of the potential of tumor cells to invade surrounding tissues, penetrate blood vessels, and ultimately enter and grow in distant tissues. Studies are directed to deciphening the signaling pathways and mechanical interactions among monocytes, macrophages, endothelial cells and carcinoma cells, and each of their supporting stroma, which contribute to the metastatic phenotype. The goals of the program are to: (1) Dissect the role the microenvironment in tumor progression and metastasis, in particular, the contribution of macrophage subpopulations to the various phases and elements of tumor progression; 2) to elucidate the molecular mechanisms of growth factor and cytokine action in regulating cell migration, dissemination, angiogenesis and invasion of distant sites by primary tumor cells; 3) to assess the role of surface molecules, such a cadherins and membrane surface oligosaccharides, in tumor progression; (4) to characterize the biochemical and structural properties of molecules that regulate cytoskeletal proteins involved in tumor cell and macrophage motility through the development of (i) fluorescent biosensors of the activity status of pathways involved in regulating cell migration in vivo and (ii) photo-switchable proteins for quantitative long-term tracking of distinct groups of cells photomarked in the primary tumor and (5) to translate these findings into correlative studies with human tissues that are predictive of metastatic potential and risk, and that identify therapeutic targets. New imaging technologies are developed in the Gruss Lipper Biophotonics Center that provides this program with unique tools that are made available to the broader AECC community through the Analytical Imaging Shared Resource. Intrinsic to the experimental approach is the development of novel mouse transgenic models with fluorescently-labeled cellular lineages. The research by members of this program is integrated by a major shared focus on breast cancer, although other tumor types are studied as well. Research in this program is supported, in part, by a program project grant which reflects, and furthers, the collaborative research of members of this program. There are currently 24 members from 11 departments, of whom 10 are new to the program, supported by 22 NCI grants ($4.1M Direct) and 18 other peer-reviewed cancer-relevant grants ($3.5M Direct). Since the last CCSG review there have been 239 cancer-relevant research papers by members of this program of which 23% represent intraprogrammatic, and 28% represent interprogrammatic publications.