Imaging and Identification of Micro-Environments Eliciting Mammary Tumor Cell Mig

达尔文的和微环境的肿瘤进展模型都有证据，但他们的直接研究 由于缺乏适当的技术，已经受到很大的阻碍。最近出现的 微环境生物传感器、光转化介导的细胞命运映射和多光子成像 活组织使这些研究在单细胞分辨率下成为可能。我们建议使用高分辨率光学技术 成像、光转换和自主纳米器件对乳房微环境的影响 肿瘤，并识别和恢复在这些肿瘤内迁移和扩散的肿瘤细胞 微环境。缺氧和炎症一直被假设为启动 肿瘤细胞的迁移、存活和扩散。在肿瘤中出现缺氧区是由于快速 细胞分裂和异常血管形成。越来越多的人认识到低氧在 通过激活血管生成、无氧酵解、侵袭和转移，在肿瘤进展的不同阶段发挥作用 转移。在项目1中，我们将使用光可切换荧光蛋白的光转换来绘制命运图 肿瘤细胞通过FIME从缺氧和炎症的微环境中扩散。我们将衡量 微环境大小和稳定性参数及其在肿瘤进展中的作用我们会收集和 描述起源于这些微环境的休眠肿瘤细胞。空间和空间的定义 这些微环境的时间范围及其对休眠的影响将允许 抑制肿瘤细胞偏头痛、扩散和转移复发的治疗策略 小分子抑制剂和抗炎药。

Evidence exists for both Darwinian and microenvironment models of tumor progression, but their direct study has been greatly hampered by the absence of appropriate technology. The recent emergence of microenvironment biosensors, photoconversion-mediated cell fate mapping, and multiphoton imaging of living tissue make these studies possible at single cell resolution. We propose to use high resolution optical imaging, photoconversion and autonomous nano-devices to deflne microenvironments in primary mammary tumors, and to identify and recover the tumor cells migrating within and disseminated from these microenvironments. Hypoxia and inflammation have been hypothesized as microenvironments that initiate tumor cell migration, survival and dissemination. Regions of oxygen deprivation arise in tumors due to rapid cell division and aberrant blood vessel formafion. Hypoxia has been increasingly recognized to play a central role in different stages of tumor progression by activating angiogenesis, anaerobic glycolysis, invasion, and metastasis. In Project 1, we will use photoconversion of photoswitchable fiuorescent proteins to fate map tumor cells disseminating from hypoxic and inflammatory microenvironments over fime. We will measure microenvironment size and stability parameters and funcfion in tumor progression. We will collect and characterize dormant tumor cells originafing in these microenvironments. The definition ofthe spatial and temporal extent of these microenvironments and their effects on dormancy will allow the development of therapeutic strategies for inhibition of tumor cell migrafion, dissemination and metastatic recurrence using small molecule inhibitors and anti-inflammatory drugs.