Reversible stem cell dormancy in the basal chordate, Botrylloides diegensis - Metastases cause 90% of cancer deaths, and can occur years to decades after eradication of the primary tumor. This is due to the remarkable ability of cancer stem cells to migrate to different tissues and transition into a dormant state, providing protection from cytotoxic therapies. Both cell intrinsic processes, as well as extrinsic signals from surrounding cells and the extracellular matrix (the niche), instruct stem cell dormancy, but the nature of these signals and the mechanisms that allow a cell to survive in a dormant state are not understood. Years later, dormant metastatic cells can awaken, but the signals regulating their re-activation are also not understood. In addition, in long-lived organisms, populations of tissue stem cells maintain themselves in a quiescent state, yet remain poised to re- activate when needed. Understanding these mechanisms have major implications for studies in both homeostatic and injury-induced tissue regeneration, and how they are dysregulated in disease and ageing. A major limitation in dissecting these processes is the absence of a system that provides the opportunity to experimentally trigger the induction and exit from a dormant state. We have developed a model in which we can precisely control when and where stem cell dormancy occurs. This organism, called Botrylloides diegensis, responds to environmental stress by resorbing its entire body, leaving only a small (3-5 mm2) vascular mat that contains both pluripotent stem cells and a complex cellular and acellular niche that supports them. Dormancy can be induced by multiple environmental triggers, including heat, cold, starvation and hypoxia, and the vascular mat can survive for months in these severe conditions. Upon return to a normal environment, the pluripotent stem cells within the vascular niche are rapidly re-activated and regenerate the entire body within days, in a process called whole body regeneration (WBR). Simply put, we can stick an animal in the refrigerator, and it will go dormant in 72 h. When we move it back to normal conditions, the stem cells are reactivated and WBR will be completed in 7 days. The stem cells can be isolated by FACS, labeled and transplanted, and the vascular mat can be live imaged. In addition, the stem cells can be selectively ablated with no effect on the ability of the niche to support WBR, allowing us to study the stem cells and niche independently. This ORIP R21 will develop a new model organism that allows studies of the interaction between stem cells and their niche at unprecedented temporal and visual resolution. These interactions are critical for understanding homeostatic and injury-induced tissue regeneration, how stem cells respond to different environmental insults, age-dependent changes in stem cell biology, and metastatic cancer recurrence.
