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

肿瘤进展的达尔文模型和微环境模型都有证据，但它们的直接研究 由于缺乏适当的技术而受到很大的阻碍。最近出现的 微环境生物传感器，光转换介导的细胞命运映射，以及微环境的多光子成像。 活组织使得这些研究在单细胞分辨率上成为可能。我们建议使用高分辨率光学 成像、光转换和自主纳米装置，以界定原发性乳腺癌的微环境 肿瘤，并识别和恢复在这些肿瘤内迁移和扩散的肿瘤细胞。 微环境缺氧和炎症被假设为微环境， 肿瘤细胞迁移、存活和扩散。缺氧区域出现在肿瘤中，由于快速的 细胞分裂和异常血管形成。人们越来越认识到缺氧在 通过激活血管生成、无氧糖酵解、侵袭， 转移在项目1中，我们将利用光转换荧光蛋白的光转换来绘制命运图， 肿瘤细胞从缺氧和炎症的微环境中扩散。我们将测量 微环境大小和稳定性参数以及肿瘤进展中的功能。我们将收集和 表征休眠的肿瘤细胞起源于这些微环境。空间的定义和 这些微环境的时间范围及其对休眠的影响将允许 抑制肿瘤细胞迁移、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.