P53-dependent stromal senescence-induced tumor dormancy in the pre-metastatic reservoir thymus

Cancer patient survival rate has significantly improved with popularization of early diagnostics and advancement in the therapy. However, after surgical removal of primary tumor and subsequent radio-chemotherapy, some cancer patients can still suffer from recurrence of the same tumor in secondary sites of the body several years later. Metastatic tumor is the major cause of death among cancer patients. This metastatic recurrence/relapse is attributed to some minimal number of tumor cells, which are able to resist radio-chemotherapy, being in sleeping/dormant state at some organs of the body. It is known that cancer cells can go to distant places of the body via vasculature and lymphatics, however, the largest lymph organ – thymus has just recently been suggested as a potential reservoir for tumor cell dormancy, and eventually relapse. However, the mechanisms responsible for tumor dormancy in the thymus are unknown. We believe that cancer cells can migrate to thymus and become dormant due to DNA damage caused by chemotherapy. Under the certain condition, those cancer cells are able to disseminate into other organs of the body leading to tumor relapse. It is necessary to study tumor micro-environmental elements in the thymus, so they could be targeted by the anti-tumor therapy. Our preliminary observation shows that administration of a chemotherapeutic drug (Doxorubicin) into young wild-type mice leads to activation of p-53 protein in thymus epithelial cells and induces thymus shrinkage. To link activation of p-53 in thymic epithelial cells and tumor dormancy we injected human breast cancer cells in young and aged mice with subsequent Doxorubicin administration. We found that tumor cells were harder to be killed in the aged involuted thymus with increased p53 in thymic epithelial cells. Our preliminary data suggest that activation of p53 in thymic epithelial cells induced by DNA-damage upon Doxorubicin promotes cell senescence of thymic epithelial cells, which leads to tumor cell dormancy/chemo-resistance. This work is clinically relevant because our findings might be able to find new strategies to prevent tumor relapse after chemotherapy.