Genetically engineered and orthotopic xenograft mouse models have been instrumental for increasing our understanding of thyroid cancer progression and for the development of novel therapeutic approaches in a setting more physiologically relevant than classical subcutaneous flank implants. However, the anatomical location of the thyroid precludes non-invasive analyses does not allow real-time evaluation of the response of tumor cells to treatments. Thus, such studies have generally only relied on endpoint approaches, limiting the amount and depth of the information that could be gathered. We have developed an innovative approach to imaging specific aspects of thyroid cancer biology, based on the implantation of a permanent, minimally invasive optical window that allows high-resolution intravital imaging of the behavior of thyroid tumors in the mouse. We show that this technology allows visualization of fluorescently tagged tumor cells in genetically engineered mouse models of anaplastic thyroid cancer (ATC) and in mice carrying orthotopic implanted human or mouse ATC cells. Furthermore, the use of recipient mice in which endothelial cells and macrophages are fluorescently labeled allows the detection of the spatial and functional relationship between tumor cells and their microenvironment. Finally, we show that ATC cells expressing a fluorescent apoptosis biosensor allow to evaluate in real time the efficacy and kinetics of action of small molecule therapeutics. This novel approach to intravital imaging of thyroid cancer represents a platform that will allow, for the first time, the longitudinal, in situ analysis of tumor cell responses to therapy and of their interaction with the microenvironment.

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