Lymph node regulation of tumor cell dormancy and reawakening

Delayed relapse affects approximately one-fifth of metastatic breast cancer patients. These metastases arise after long asymptomatic periods lasting five or more years before emerging in secondary locations. It thought that disseminated tumor cells (DTCs) seed these sites early on where they become quiescent until reawakened by an unknown trigger. Since the latency period is a prime treatment window to target dormant DTCs, it is critical to understand what initiates DTC dormancy and what causes them to reawaken. The microenvironment has been shown to regulate dormancy in the lung and bone marrow yet little is known about the lymph node dormancy niche although it is the earliest and most common site of metastasis. To investigate lymph node-specific mechanisms of dormancy, mouse and cell culture models of dormancy were used to demonstrate that lymph node endothelia promote DTC quiescence. Since the lymph node niche is prone to expansion and remodeling due to inflammation, loss of stable endothelial architecture during infection was hypothesized to induce dormancy reversal and DTC outgrowth. This hypothesis will be tested in animal models and in a co-culture system that mimics the lymphovasculature to identify signals that promote dormant DTC reawakening, which may reveal new targets for therapeutic intervention.