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.
Use of new photoconversion technology to fate map tumor cells disseminafing from hypoxic and inflammatory microenvironments will be used to collect and characterize dormant tumor cells in vivo. The definifion of the spafial and temporal extent of these microenvironments and their tumor stroma dependence will allow the development of therapeutic strategies for inhibition of tumor cell migration, dissemination and metastatic recurrence using small molecule inhibitors and anti-inflammatory drugs.
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